Gene Summary

Gene:IGH; immunoglobulin heavy locus
Summary:Immunoglobulins recognize foreign antigens and initiate immune responses such as phagocytosis and the complement system. Each immunoglobulin molecule consists of two identical heavy chains and two identical light chains. This region represents the germline organization of the heavy chain locus. The locus includes V (variable), D (diversity), J (joining), and C (constant) segments. During B cell development, a recombination event at the DNA level joins a single D segment with a J segment; this partially rearranged D-J gene is then joined to a V segment. The rearranged V-D-J is then transcribed with the IGHM constant region; this transcript encodes a mu heavy chain. Later in development B cells generate V-D-J-Cmu-Cdelta pre-messenger RNA, which is alternatively spliced to encode either a mu or a delta heavy chain. Mature B cells in the lymph nodes undergo switch recombination, so that the V-D-J gene is brought in proximity to one of the IGHG, IGHA, or IGHE genes and each cell expresses either the gamma, alpha, or epsilon heavy chain. Recombination of many different V segments with several J segments provides a wide range of antigen recognition. Additional diversity is attained by junctional diversity, resulting from the random addition of nucleotides by terminal deoxynucleotidyltransferase, and by somatic hypermutation, which occurs during B cell maturation in the spleen and lymph nodes. Due to polymorphism, the numbers of functional V, J, and D genes differ among individuals and some V, D, J, and C segments may be pseudogenes. [provided by RefSeq, Dec 2017]
Databases:OMIM, HGNC, GeneCard, Gene
Source:NCBIAccessed: 31 August, 2019

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (13)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Lymphoma, Mantle-Cellt(11;14)(q13;q32) in Mantle Cell Lymphoma
Mantle cell lymphoma (MCL) is characterised by a t(11;14)(q13;q32) translocation. This juxtaposes the CCND1 (bcl-1) locus to the immunoglobulin (IgH) gene sequences and leads to deregulation of cyclin D1. See Espinet B, et al, 1999 and Stamatopoulos K, et al, 1999.
View Publications479
Multiple MyelomaIGH and Multiple Myeloma View Publications316
Acute Lymphocytic Leukaemia (ALL)IGH and Acute Lymphocytic Leukaemia View Publications270
Chronic Lymphocytic LeukemiaIGH and Chronic Lymphocytic Leukemia View Publications178
MALT LymphomaIGH and MALT Lymphoma View Publications139
Lymphoma, Mantle-CellIGH and Mantle-Cell Lymphoma
In a GWAS study Bea et al (2013) reported IGHV mutations in 41% (12/29) of MTC cases.
View Publications76
Lymphomat(6;14)(p25,q32) in Lymphomas
This translocation is seen in some B-cell non Hodgkin lymphomas, particular in diffuse large B-cell lymphoma.
View Publications50
Waldenstrom's MacroglobulinemiaIGH and Waldenstrom's Macroglobulinemia View Publications24
-IGH and Splenic Neoplasms View Publications17
Non-Hodgkin Lymphomat(1;14)(q21;q32) and MUC1 Overexpression in NHL
Dyomin et al (2000) and Gilles et al (2000) reported that MUC1 is activated in Non-Hodgkin's lymphoma by the t(1;14)(q21;q32) translocation and is rearranged and amplified in B-cell lymphomas.
View Publications15
Multiple Myelomat(6;14)(p25;q32) in Myeloma
This translocation juxtaposes the IgH locus to the IRF4 gene resulting in overexpressed of IRF4, which is thought to contribute to tumorigenesis in Myeloma.
View Publications15
-t(11;14)(q23;q32) IGH-DDX6 Translocations in Hematologic Cancers View Publications1
Non-Hodgkin Lymphomat(1;14)(q21;q32) BCL9/IGH

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: IGH (cancer-related)

Tian L, Shao Y, Nance S, et al.
Long-read sequencing unveils IGH-DUX4 translocation into the silenced IGH allele in B-cell acute lymphoblastic leukemia.
Nat Commun. 2019; 10(1):2789 [PubMed] Free Access to Full Article Related Publications
IGH@ proto-oncogene translocation is a common oncogenic event in lymphoid lineage cancers such as B-ALL, lymphoma and multiple myeloma. Here, to investigate the interplay between IGH@ proto-oncogene translocation and IGH allelic exclusion, we perform long-read whole-genome and transcriptome sequencing along with epigenetic and 3D genome profiling of Nalm6, an IGH-DUX4 positive B-ALL cell line. We detect significant allelic imbalance on the wild-type over the IGH-DUX4 haplotype in expression and epigenetic data, showing IGH-DUX4 translocation occurs on the silenced IGH allele. In vitro, this reduces the oncogenic stress of DUX4 high-level expression. Moreover, patient samples of IGH-DUX4 B-ALL have similar expression profile and IGH breakpoints as Nalm6, suggesting a common mechanism to allow optimal dosage of non-toxic DUX4 expression.

Murase T, Ri M, Narita T, et al.
Immunohistochemistry for identification of CCND1, NSD2, and MAF gene rearrangements in plasma cell myeloma.
Cancer Sci. 2019; 110(8):2600-2606 [PubMed] Free Access to Full Article Related Publications
The t(11;14)/CCND1-IGH, t(4;14)/NSD2(MMSET)-IGH, and t(14;16)/IGH-MAF gene rearrangements detected by fluorescence in situ hybridization (FISH) are used for risk stratification in patients with multiple myeloma (MM). Compared with conventional FISH techniques using fresh cells, immunohistochemistry (IHC) is much more cost- and time-efficient, and can be readily applied to routinely prepared formalin-fixed, paraffin-embedded (FFPE) materials. In this study, we performed tissue FISH and IHC employing FFPE specimens, and examined the usefulness of IHC as a tool for detecting CCND1, NSD2, and MAF gene rearrangements. CD138 signals were used to identify plasma cells in tissue FISH and IHC analyses. With cohort 1 (n = 70), we performed tissue FISH and subsequently IHC, and determined IHC cut-off points. In this cohort, the sensitivity and specificity for the 3 molecules were ≥.90 and ≥.96, respectively. With cohort 2, using MM cases with an unknown gene status (n = 120), we performed IHC, and the gene status was estimated using the cut-off points determined with cohort 1. The subsequent FISH analysis showed that the sensitivity and specificity for the 3 molecules were ≥.92 and ≥.98, respectively. CCND1, NSD2, and MAF gene rearrangements were estimated accurately by IHC, suggesting that conventional FISH assays can be replaced by IHC.

Li X, Wu N, Li B
A high mutation rate of immunoglobulin heavy chain variable region gene associates with a poor survival and chemotherapy response of mantle cell lymphoma patients.
Medicine (Baltimore). 2019; 98(22):e15811 [PubMed] Related Publications
Immunoglobulin heavy chain variable region (IGHV) gene mutation status is a biomarker for the prognosis of chronic lymphocytic leukemia, whether it is associated with the diagnosis, staging, and prognosis of patients with mantle cell lymphoma (MCL) remains to be determined.The IGHV gene mutations of 52 MCL patients were determined by DNA sequencing and compared with published IGHV germline sequences.DNA sequence alignment of IGHV variable regions with published IGHV germline sequences showed that the coincidence rate was 94% to 100%. Ten cases (21%) were significantly mutated with the rate of 96.9% to 94.0%. The overall survival time of patients was negatively correlated with the degree of IGHV gene mutation. Further survival analysis with log-rank test demonstrated that the patients with significant IGHV gene mutations showed a trend towards poor survival.The mutation rate of the IGHV variant region may be determined to assess the prognosis and overall survival time of MCL patients.

Lu G, Qiao L, Li D, et al.
Concurrent lymphoma and hemophilia B in a pediatric patient: A case report.
Medicine (Baltimore). 2019; 98(19):e15474 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Lymphoma is the third most common cancer among children in the United States and Europe. Hemophilia is a congenital bleeding disorder characterized by deficiency of coagulation factor VIII or IX. Hemophilia B is a consequence of factor IX deficiency and has an incidence of 1 in 20,000 male births. A concurrence of these 2 uncommon diseases is rare except in patients infected with the human immunodeficiency virus (HIV). We report a case of a patient with both Burkitt lymphoma and hemophilia B; this is only such report in China since 1987.
PATIENT CONCERNS: A 3-year-old boy was admitted to our hospital because of melena and jaundice for several days. His older brother had died due to hemophilia B and ventricular septal defect. The patient had not experienced any previous episodes of severe bleeding. Gradual abdominal distention was observed after admission; the patient's superficial lymph nodes were not enlarged. Results of blood routine and bone marrow examinations showed no abnormalities. He was diagnosed with sclerosing cholangitis, abdominal infection, and hepatitis. However, after treatment of reducing enzyme activity and eliminating jaundice, the patient's condition deteriorated. Hydrops abdominis was detected on abdominal ultrasonography. Tumor cells were found by pathological examination of peritoneal effusion. Both a c-myc gene translocation and a c-myc-IgH gene fusion were detected.
DIAGNOSIS: Burkitt lymphoma and hemophilia B.
INTERVENTIONS: The patient was transferred to the Pediatric Hematology Department of our hospital and treated with a modified B-NHL-BFM-95 protocol. During chemotherapy, platelet changes were monitored regularly and blood products were infused timely.
OUTCOMES: The patient died of infection and bleeding after chemotherapy.
CONCLUSION: Concurrent hemophilia and lymphoma are rare, especially in children. When encountering a patient with unexplained obstructive jaundice and massive ascites, the possibility of a tumor should be considered. Early diagnosis and adequate treatment of such tumor may improve prognosis.

Bilous N, Abramenko I, Chumak A, et al.
Analysis of LPL gene expression in patients with chronic lymphocytic leukemia.
Exp Oncol. 2019; 41(1):39-45 [PubMed] Related Publications
AIM: The IGHV mutational status is one of the most important markers for chronic lymphocytic leukemia (CLL) prognostication. Lipoprotein lipase (LPL) gene expression was found to correlate with IGHV status and was suggested as its surrogate marker. Recent data reported that LPL expression might be influenced by pivotal signalling pathways in CLL. This study aimed to assess LPL gene expression in relation to key immunogenetic and molecular markers of CLL, including IGHV mutational status, B-cell receptor (BCR) stereotypy, TP53, NOTCH1, and SF3B1 gene mutations. Materials and Methods: Expression of LPL mRNA was measured in peripheral blood mononuclear cells of 73 CLL patients by real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR). IGHV, NOTCH1, TP53, and SF3B1 gene mutation analysis was performed by PCR amplification and direct sequencing.
RESULTS: 44 of 73 (60%) CLL cases were categorized as LPL-positive based on the cut-off value established by ROC (receiver operating characteristic) curve analysis. LPL expression was significantly associated with IGHV mutation status (r = 0.684; p < 0.0001) and tended to correlate with presence of NOTCH1 gene mutations (p = 0.113). BCR stereotyped cases showed higher LPL expression values in comparison to unstereotyped cases in the LPL-positive group of patients (p = 0.041). LPL expression was associated with a shorter overall survival in the entire СLL group (median 107 vs 143, p = 0.048) as well as in Binet A patients, albeit with borderline significance (median 139 vs not reached, p = 0.086).
CONCLUSION: LPL expression was found to be closely correlated with IGHV gene mutational status and overall survival, proving LPL as prognostic marker in CLL. Our results also indicate a possible relationship between aberrant expression of LPL and BCR- and NOTCH1-dependent signalling pathways.

López C, Kleinheinz K, Aukema SM, et al.
Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma.
Nat Commun. 2019; 10(1):1459 [PubMed] Free Access to Full Article Related Publications
Burkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset of BL is a B-cell poised to express IGHA. We describe the landscape of mutations, structural variants, and mutational processes, and identified a series of driver genes in the pathogenesis of BL, which can be targeted by various mechanisms, including IG-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing.

Nishio Y, Sakai H, Saiki Y, et al.
Light-chain plasma cell myeloma caused by 14q32/IGH translocation and loss of the other allele.
Int J Hematol. 2019; 109(5):572-577 [PubMed] Related Publications
Light-chain plasma cell myeloma (LC-PCM) is a PCM subtype in which only immunoglobulin light-chain is secreted. However, the absence of immunoglobulin heavy-chain (IGH) production in this condition has not been fully elucidated. To address this issue, we retrospectively analyzed patients at our center with LC-PCM and found a group who had only split signals of IGH gene derived from 14q32/IGH translocations by fluorescence in situ hybridization (FISH). Six patients were identified with only split signals of the IGH gene derived from 14q32/IGH translocations. Five of these patients were newly diagnosed, while one had IgG-λ PCM at presentation, which transformed to λ LC-PCM after treatment. The translocation partners were identified in four patients: two cases of (11;14)(q13;q32) and two cases of (4;14)(p16;q32). The development of LC-PCM appears to be explained by the application of allelic exclusion in these patients, such that 14q32/IGH translocation in one allele contributes to the pathogenesis of PCM and the subsequent loss of the other allele is responsible for the loss of IGH production. These findings suggest that a FISH pattern of IGH with "split and loss" may constitute a unique subgroup of LC-PCM.

Daniele G, L'Abbate A, Turchiano A, et al.
1q23.1 homozygous deletion and downregulation of Fc receptor-like family genes confer poor prognosis in chronic lymphocytic leukemia.
Clin Exp Med. 2019; 19(2):261-267 [PubMed] Related Publications
The identification of chromosome 1 translocations and deletions is a rare and poorly investigated event in chronic lymphocytic leukemia (CLL). Nevertheless, the identification of novel additional molecular alterations is of great interest, opening to new prognostic and therapeutic strategies for such heterogeneous hematological disease. We here describe a patient affected by CLL with a mutated IGHV status, showing a balanced t(1;3)(q23.1;q21.3) translocation and a der(18)t(1;18)(q24.2;p11.32), accompanying the recurrent 13q14 heterozygous deletion in all analyzed cells at onset. By combining whole-genome sequencing, SNP array, RNA sequencing, and FISH analyses, we defined a 1q23.1 biallelic minimally deleted region flanking translocations breakpoints at both derivative chromosome 1 homologues. The deletion resulted in the downregulation of the Fc receptor-like family genes FCRL1, FCRL2, and FCRL3 and in the lack of expression of FCRL5, observed by RT-qPCR. The mutational status of TP53, NOTCH1, SF3B1, MYD88, FBXW7, and XPO1 was investigated by targeted next-generation sequencing, detecting a frameshift deletion within NOTCH1 (c.7544_7545delCT). We hypothesize a loss of tumor suppressor function for FCRL genes, cooperating with NOTCH1 mutation and 13q14 genomic loss in our patient, both conferring a negative prognosis, independently from the known biological prognostic factors of CLL.

Pott C, Brüggemann M, Ritgen M, et al.
MRD Detection in B-Cell Non-Hodgkin Lymphomas Using Ig Gene Rearrangements and Chromosomal Translocations as Targets for Real-Time Quantitative PCR.
Methods Mol Biol. 2019; 1956:199-228 [PubMed] Related Publications
Minimal residual disease (MRD) diagnostics is of high clinical relevance in patients with indolent B-cell non-Hodgkin lymphomas (B-NHL) and serves as a surrogate parameter to evaluate treatment effectiveness and long-term prognosis. MRD diagnostics performed by real-time quantitative PCR (RQ-PCR) is still the gold standard and currently the most sensitive and the most broadly applied method in follicular lymphoma (FL) and mantle cell lymphoma (MCL). Alternatively, droplet digital PCR (ddPCR) can be used for MRD monitoring in multiple myeloma, mantle cell lymphoma, and follicular lymphoma with comparable sensitivity, accuracy, and reproducibility.The most broadly applicable MRD target in B-NHL is the junctional regions of the rearranged immunoglobulin heavy chain gene (IGHV). Chromosomal translocations like the t(14;18) translocation in FL and t(11;14) translocation in MCL can be used as MRD target in selected lymphoma subtypes. In patients with B-cell chronic lymphocytic leukemia, both flow-cytometry and RQ-PCR are equally suited for MRD assessment as long as a sensitivity of 10

Küppers R, Schneider M, Hansmann ML
Laser-Based Microdissection of Single Cells from Tissue Sections and PCR Analysis of Rearranged Immunoglobulin Genes from Isolated Normal and Malignant Human B Cells.
Methods Mol Biol. 2019; 1956:61-75 [PubMed] Related Publications
Normal and malignant B cells carry rearranged immunoglobulin (Ig) variable region genes, which due to their practically limitless diversity represent ideal clonal markers for these cells. We describe here an approach to isolate single cells from frozen tissue sections by microdissection using a laser-based method. From the isolated cells, rearranged IgH and Igκ genes are amplified in a semi-nested PCR approach, using a collection of V gene subgroup-specific primers recognizing nearly all V genes together with primers for the J genes. By sequence analysis of V region genes from distinct cells, the clonal relationship of the B lineage cells can unequivocally be determined and related to the histological distribution of the cells. The approach is also useful to determine V, D, and J gene usage. Moreover, the presence and pattern of somatic Ig V gene mutations give valuable insight into the stage of differentiation of the B cells.

Hu X, Zhang J, Wang J, et al.
Landscape of B cell immunity and related immune evasion in human cancers.
Nat Genet. 2019; 51(3):560-567 [PubMed] Related Publications
Tumor-infiltrating B cells are an important component in the microenvironment but have unclear anti-tumor effects. We enhanced our previous computational algorithm TRUST to extract the B cell immunoglobulin hypervariable regions from bulk tumor RNA-sequencing data. TRUST assembled more than 30 million complementarity-determining region 3 sequences of the B cell heavy chain (IgH) from The Cancer Genome Atlas. Widespread B cell clonal expansions and immunoglobulin subclass switch events were observed in diverse human cancers. Prevalent somatic copy number alterations in the MICA and MICB genes related to antibody-dependent cell-mediated cytotoxicity were identified in tumors with elevated B cell activity. The IgG3-1 subclass switch interacts with B cell-receptor affinity maturation and defects in the antibody-dependent cell-mediated cytotoxicity pathway. Comprehensive pancancer analyses of tumor-infiltrating B cell-receptor repertoires identified novel tumor immune evasion mechanisms through genetic alterations. The IgH sequences identified here are potentially useful resources for future development of immunotherapies.

Stuhlmann-Laeisz C, Schönland SO, Hegenbart U, et al.
AL amyloidosis with a localized B cell neoplasia.
Virchows Arch. 2019; 474(3):353-363 [PubMed] Related Publications
Immunoglobulin light chain-derived (AL) amyloidosis may occur as a systemic disease usually with dismal prognosis and a localized variant with favorable outcome. We report 29 patients with AL amyloidosis and associated lymphoplasmacytic infiltrate spatially related to amyloid deposits. In 17 cases, the amyloid deposits were classified as ALλ and 12 as ALκ Histopathology in all cases showed relatively sparse plasma cells and B cells without tumor or sheet formation by the lymphoplasmacytic infiltrate. The B cells predominantly showed an immunophenotype of the marginal zone. In situ, hybridization revealed 17 cases with λ- and 10 with κ light chain restricted plasma cells, which was concordant with the AL subtype in each case. Clonal immunoglobulin heavy variable gene (IGHV) or κ light chain rearrangement was found in 23/29 interpretable cases. A single case harbored a MYD88

Govindasamy P, Pandurangan P, Tarigopula A, et al.
Cytogenetic Abnormalities in Multiple Myeloma Patients at a Tertiary Healthcare Center in India
Asian Pac J Cancer Prev. 2019; 20(1):235-241 [PubMed] Free Access to Full Article Related Publications
Objective: Multiple myeloma (MM) is a clinically and genetically heterogeneous plasma cell neoplasm. The prognosis of MM patients is dependent on several factors including the patient’s age, the stage of disease and genetic alterations. This study aimed to determine the frequency of common chromosomal abnormalities and their significance in MM patients referred to a tertiary healthcare center in India. Methods: Fluorescence in situ hybridization on interphase nuclei from bone marrow cells using seven MM-specific probes for recurrent aberrations was performed in a total of 215 newly diagnosed patients. Results: Chromosomal abnormalities were detected in 161 (74.9%) MM patients in this study. The most frequent aberration was trisomy(ies) involving only gain of chromosomes in 48 (22.3%) cases. A translocation involving the IGH gene alone or accompanied by trisomy(ies) or by monosomy 13/13q deletion or by both was registered in 80 (37.2%) patients. Atypical patterns such as a deletion of the IGH variable segment (IGHv) on the derivative chromosome 14 or on the native (normal) chromosome 14, biallelic deletion of IGHv, deletion of the IGH constant segment on the rearranged chromosome14 and extra fusions were noticed in 21 (9.8%) patients with an IGH rearrangement. Monosomy 13/deletion 13q was identified singly or as part of a complex karyotype in 74 patients (34.4%). Clonal heterogeneity and additional abnormalities including TP53 deletion and monosomies of chromosomes 4, 9, 14 and 16 were recorded in 18.6% and 16.3% of patients respectively. Patients with abnormalities exhibited plasmacytosis, reduced hemoglobin value and high level of ß2-microglobulin. Conclusions: A lower median age and a low frequency of IGH translocations particularly t(11;14) and chromosome 13 abnormalities suggest ethnic diversity. Further investigations on genetic alterations including IGH deletions will contribute to improved insights into the biology of myeloma disease, risk stratification and patient management.

Stratmann JA, von Rose AB, Koschade S, et al.
Clinical and genetic characterization of de novo double-hit B cell precursor leukemia/lymphoma.
Ann Hematol. 2019; 98(3):647-656 [PubMed] Related Publications
The 2016 revised World Health Organization (WHO) classification of lymphoid neoplasms included the category of high-grade B cell lymphomas (HGBLs) with combined MYC and BCL2 and/or BCL6 rearrangements (double-hit, DH). However, the clinical features of B cell precursor leukemia (BCP-ALL) that harbor DH genetics remain widely unknown. We performed a retrospective analysis of the German Multicenter Study Group for Adult ALL registry and a literature search for de novo DH-BCP-ALLs. We identified 6 patients in the GMALL registry and 11 patients published in the literature between 1983 and June 2018. Patients of all ages (range, 15-86 years) are affected. There is a high incidence of meningeal disease and other extramedullary disease manifestations. Current treatment approaches are mainly ALL-based and are sufficient to induce first complete remissions, but progression-free survival is only 4.0 months (95% CI, 1.5-6.5 months) and all patients succumb to their disease, once relapsed, with a median survival of 5.0 months (95% CI, 3.1-6.9 months), despite intensive salvage and targeted therapy approaches. Of all patients, only two that attained an initial complete remission were alive at data cutoff. In all cases, the BCL2 gene was rearranged to be in proximity to the IGH locus, whereas MYC had various translocation partners juxtaposed. There was no significant survival difference between IG and non-IG translocation partners (HR, 1.03; 95% CI, 0.33-3.2; p = 0.89). In conclusion, de novo DH-BCP-ALL is an aggressive B cell malignancy with deleterious outcome. Physicians have to be aware of this rare disease subset due to the atypical clinical behavior and especially because latest classification systems do not cover this sub-entity.

Hu T, Shen J, Liu W, Zheng Z
Multiple myeloma secondary to acute lymphoblastic leukemia: A case report.
Medicine (Baltimore). 2019; 98(1):e14018 [PubMed] Free Access to Full Article Related Publications
RATIONALE: Acute lymphoblastic leukemia (ALL) secondary to multiple myeloma (MM) is rare. Here we report a rare case of secondary ALL transformed from MM.
PATIENT CONCERNS: A 64-year-old woman was diagnosed as MM IgG light chain type in 2001. She achieved complete remission after 2 cycles of therapy, and received maintenance therapy with thalidomide. The patient suffered from MM relapse in September 2011. Bone marrow examination showed that the percentage of primary lymphocytes was 59%, indicating ALL-L2 (Pre-B-ALL). The patient reached complete remission after 1 cycle of chemotherapy, and has been maintained for more than 6 years.
DIAGNOSES: Immunophenotyping analysis revealed that the abnormal cell population accounted for approximately 66% which expressed HLA-DR, CD4, CD22, CD33, CD34, and cCD79a. These results indicated acute B lymphoblastic leukemia. Chromosome presented 47, XX, +5, -7, +19. Leukemia fusion gene analysis demonstrated positive EVI1 and negative IgH and TCR gene rearrangement.
INTERVENTIONS: The patient accepted 1 cycle of VDCLP chemotherapy and reached complete remission, followed with consolidation therapies with VDCLP, MA, CAG and other chemotherapy regimens.
OUTCOMES: This patient has maintained CR1 of ALL for more than 6 years.
LESSONS: Even secondary lymphoblastic leukemia has been rarely reported in patients with MM, we still need perform bone marrow examination, flow cytology, and gene tests, especially during maintenance therapy.

Oh G, Koncevičius K, Ebrahimi S, et al.
Circadian oscillations of cytosine modification in humans contribute to epigenetic variability, aging, and complex disease.
Genome Biol. 2019; 20(1):2 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Maintenance of physiological circadian rhythm plays a crucial role in human health. Numerous studies have shown that disruption of circadian rhythm may increase risk for malignant, psychiatric, metabolic, and other diseases.
RESULTS: Extending our recent findings of oscillating cytosine modifications (osc-modCs) in mice, in this study, we show that osc-modCs are also prevalent in human neutrophils. Osc-modCs may play a role in gene regulation, can explain parts of intra- and inter-individual epigenetic variation, and are signatures of aging. Finally, we show that osc-modCs are linked to three complex diseases and provide a new interpretation of cross-sectional epigenome-wide association studies.
CONCLUSIONS: Our findings suggest that loss of balance between cytosine methylation and demethylation during the circadian cycle can be a potential mechanism for complex disease. Additional experiments, however, are required to investigate the possible involvement of confounding effects, such as hidden cellular heterogeneity. Circadian rhythmicity, one of the key adaptations of life forms on Earth, may contribute to frailty later in life.

Potter N, Jones L, Blair H, et al.
Single-cell analysis identifies CRLF2 rearrangements as both early and late events in Down syndrome and non-Down syndrome acute lymphoblastic leukaemia.
Leukemia. 2019; 33(4):893-904 [PubMed] Free Access to Full Article Related Publications
Deregulated expression of the type I cytokine receptor, CRLF2, is observed in 5-15% of precursor B-cell acute lymphoblastic leukaemia (B-ALL). We have previously reported the genomic landscape of patients with CRLF2 rearrangements (CRLF2-r) using both whole genome and exome sequencing, which identified a number of potential clonal and sub-clonal genomic alterations. In this study, we aimed to assess when the CRLF2-r; IGH-CRLF2 or P2RY8-CRLF2, arose during the evolution of both Down syndrome-ALL (DS-ALL) and non-DS-ALL. Using fluorescence in situ hybridisation, we were able to track up to four structural variants in single cells from 47 CRLF2-r B-ALL patients, which in association with our multiplex single-cell analysis of a further four patients, permitted simultaneous tracking of copy number alterations, structural and single nucleotide variants within individual cells. We observed CRLF2-r arising as both early and late events in DS and non-DS-ALL patients. Parallel evolution of discrete clones was observed in the development of CRLF2-r B-ALL, either involving the CRLF2-r or one of the other tracked abnormalities. In-depth single-cell analysis identified both linear and branching evolution with early clones harbouring a multitude of abnormalities, including the CRLF2-r in DS-ALL patients.

Li JF, Dai YT, Lilljebjörn H, et al.
Transcriptional landscape of B cell precursor acute lymphoblastic leukemia based on an international study of 1,223 cases.
Proc Natl Acad Sci U S A. 2018; 115(50):E11711-E11720 [PubMed] Free Access to Full Article Related Publications
Most B cell precursor acute lymphoblastic leukemia (BCP ALL) can be classified into known major genetic subtypes, while a substantial proportion of BCP ALL remains poorly characterized in relation to its underlying genomic abnormalities. We therefore initiated a large-scale international study to reanalyze and delineate the transcriptome landscape of 1,223 BCP ALL cases using RNA sequencing. Fourteen BCP ALL gene expression subgroups (G1 to G14) were identified. Apart from extending eight previously described subgroups (G1 to G8 associated with

Fries C, Burack WR
A clinical perspective on immunoglobulin heavy chain clonal heterogeneity in B cell acute lymphoblastic leukemia.
Leuk Res. 2018; 75:15-22 [PubMed] Related Publications
B cell acute lymphoblastic leukemia (B ALL) is a genetically heterogeneous neoplasm often demonstrating extensive subclone diversity within each patient's disease. The immunoglobulin heavy chain (IGH) locus is a marker of clonal variation in B ALL due to its intrinsic role in B lymphocyte development and its diverse Vh(D)Jh rearrangement patterns. B ALL IGH evolution may contribute to limitations in minimal residual disease (MRD) monitoring methods. Evolving technologies for IGH high-throughput sequencing (HTS) have demonstrated MRD detection as sensitive as 1 cell in 1,000,000. These methods may enhance the surveillance of B ALL in the setting of extensive subclone evolution and provide opportunities for detection and intervention before the onset of relapse. However, HTS MRD methods will need to be evaluated in the context of clinical trials in order to gain further insights about the clinical relevance of such sensitive B ALL MRD detection.

Pugh TJ, Fink JM, Lu X, et al.
Assessing genome-wide copy number aberrations and copy-neutral loss-of-heterozygosity as best practice: An evidence-based review from the Cancer Genomics Consortium working group for plasma cell disorders.
Cancer Genet. 2018; 228-229:184-196 [PubMed] Related Publications
BACKGROUND: Plasma cell neoplasms (PCNs) encompass a spectrum of disorders including monoclonal gammopathy of undetermined significance, smoldering myeloma, plasma cell myeloma, and plasma cell leukemia. Molecular subtypes have been defined by recurrent cytogenetic abnormalities and somatic mutations that are prognostic and predictive. Karyotype and fluorescence in situ hybridization (FISH) have historically been used to guide management; however, new technologies and markers raise the need to reassess current testing algorithms.
METHODS: We convened a panel of representatives from international clinical laboratories to capture current state-of-the-art testing from published reports and to put forward recommendations for cytogenomic testing of plasma cell neoplasms. We reviewed 65 papers applying FISH, chromosomal microarray (CMA), next-generation sequencing, and gene expression profiling for plasma cell neoplasm diagnosis and prognosis. We also performed a survey of our peers to capture current laboratory practice employed outside our working group.
RESULTS: Plasma cell enrichment is widely used prior to FISH testing, most commonly by magnetic bead selection. A variety of strategies for direct, short- and long-term cell culture are employed to ensure clonal representation for karyotyping. Testing of clinically-informative 1p/1q, del(13q) and del(17p) are common using karyotype, FISH and, increasingly, CMA testing. FISH for a variety of clinically-informative balanced IGH rearrangements is prevalent. Literature review found that CMA analysis can detect abnormalities in 85-100% of patients with PCNs; more specifically, in 5-53% (median 14%) of cases otherwise normal by FISH and cytogenetics. CMA results in plasma cell neoplasms are usually complex, with alteration counts ranging from 1 to 74 (median 10-20), primarily affecting loci not covered by FISH testing. Emerging biomarkers include structural alterations of MYC as well as somatic mutations of KRAS, NRAS, BRAF, and TP53. Together, these may be measured in a comprehensive manner by a combination of newer technologies including CMA and next-generation sequencing (NGS). Our survey suggests most laboratories have, or are soon to have, clinical CMA platforms, with a desire to move to NGS assays in the future.
CONCLUSION: We present an overview of current practices in plasma cell neoplasm testing as well as an algorithm for integrated FISH and CMA testing to guide treatment of this disease.

Jo I, Chung NG, Lee S, et al.
Considerations for monitoring minimal residual disease using immunoglobulin clonality in patients with precursor B-cell lymphoblastic leukemia.
Clin Chim Acta. 2019; 488:81-89 [PubMed] Related Publications
BACKGROUND: Minimal residual disease (MRD) monitoring is a powerful tool to predict the risk of relapse. Herein, we present an MRD monitoring strategy for B-cell lymphoblastic leukemia (B-ALL) using high-throughput sequencing (HTS) of immunoglobulin (Ig) clonality before implementation into routine practice.
METHODS: We selected 74 bone marrow (BM) specimens from 47 patients who were diagnosed with B-ALL. Ig clonality was analyzed using both fragment analysis and HTS. The performance of Ig clonality was evaluated through comparison of the results from real-time quantitative polymerase chain reaction (qPCR) of leukemia-specific fusion transcripts and flow cytometry.
RESULTS: IGH clonality was observed in all patients, and the sum of clonal burden varied (9.47%-96.77%). IGK clonality was identified in 70% of patients and availed in cases with low IGH clonal burden. The total IGH clonal burden was significantly correlated with the proportion of leukemic blasts, leukemia-specific fusion transcripts, and flow cytometry. We recognized the different responses of each clone and emerging clones originating from the trace of Ig rearrangement presented in the initial specimen. IGH clonal burden after chemotherapy represented patient outcomes well. IGH assay also provided information of repertoire diversity of IGH rearrangement.
CONCLUSION: The Ig clonality assay via HTS will be a promising tool for MRD monitoring of B-ALL through an adequate strategy to identify and monitor individual clones and determine repertoire diversity.

Theunissen PMJ, de Bie M, van Zessen D, et al.
Next-generation antigen receptor sequencing of paired diagnosis and relapse samples of B-cell acute lymphoblastic leukemia: Clonal evolution and implications for minimal residual disease target selection.
Leuk Res. 2019; 76:98-104 [PubMed] Related Publications
Antigen receptor gene rearrangements are frequently applied as molecular targets for detection of minimal residual disease (MRD) in B-cell precursor acute lymphoblastic leukemia patients. Since such targets may be lost at relapse, appropriate selection of antigen receptor genes as MRD-PCR target is critical. Recently, next-generation sequencing (NGS) - much more sensitive and quantitative than classical PCR-heteroduplex approaches - has been introduced for identification of MRD-PCR targets. We evaluated 42 paired diagnosis-relapse samples by NGS (IGH, IGK, TRG, TRD, and TRB) to evaluate clonal evolution patterns and to design an algorithm for selection of antigen receptor gene rearrangements most likely to remain stable at relapse. Overall, only 393 out of 1446 (27%) clonal rearrangements were stable between diagnosis and relapse. If only index clones with a frequency >5% at diagnosis were taken into account, this number increased to 65%; including only index clones with an absolute read count >10,000, indicating truly major clones, further increased the stability to 84%. Over 90% of index clones at relapse were also present as index clone at diagnosis. Our data provide detailed information about the stability of antigen receptor gene rearrangements, based on which we propose an algorithm for selecting stable MRD-PCR targets, successful in >97% of patients.

Hattori K, Sakata-Yanagimoto M, Kusakabe M, et al.
Genetic evidence implies that primary and relapsed tumors arise from common precursor cells in primary central nervous system lymphoma.
Cancer Sci. 2019; 110(1):401-407 [PubMed] Free Access to Full Article Related Publications
Primary central nervous system lymphoma (PCNSL) is a rare subtype of lymphoma that arises within the brain or the eyes. PCNSL recurs within the central nervous system (CNS) in most relapsed cases, whereas extra-CNS relapse is experienced in rare cases. The present study aimed at identifying the presence of common precursor cells (CPC) for primary intra- and relapsed extra-CNS tumors, and further assessing the initiating events in bone marrow (BM). Targeted deep sequencing was carried out for five paired primary intra- and relapsed extra-CNS tumors of PCNSL. Two to five mutations were shared by each pair of intra- and extra-CNS tumors. In particular, MYD88 mutations, L265P in three and P258L in one, were shared by four pairs. Unique somatic mutations were observed in all five intra-CNS tumors and in four out of five extra-CNS tumors. Remarkably, IgH clones in the intra- and the extra-CNS tumors in two pairs were distinct from each other, whereas one pair of tumors shared identical monoclonal IgH rearrangement. In a cohort of 23 PCNSL patients, L265P MYD88 mutations were examined in tumor-free BM mononuclear cells (MNC) in which the PCNSL tumors had L265P MYD88 mutations. L265P MYD88 mutations were detected by a droplet digital PCR method in nine out of 23 bone marrow mononuclear cells. These results suggest that intra- and extra-tumors are derived from CPC with MYD88 mutations in most PCNSL, arising either before or after IgH rearrangement. The initiating MYD88 mutations may occur during B-cell differentiation in BM.

Yuan YY, Zhu HY, Wu JZ, et al.
The percentage of cells with 17p deletion and the size of 17p deletion subclones show prognostic significance in chronic lymphocytic leukemia.
Genes Chromosomes Cancer. 2019; 58(1):43-51 [PubMed] Related Publications
TP53 disruption is considered to be the most important prognostic factor in chronic lymphocytic leukemia (CLL), but not all patients with TP53 disruption have similar dismal outcomes. We evaluated the prognostic value of TP53 disruption in CLL patients without treatment indications. Data of 305 CLL patients were analyzed. 41 of them (13%) had TP53 disruption. Patients with lower percentage of cells with del(17p) had significantly better survival. Patients with mutated IGHV, β2-microglobulin ≤3.5 mg/L, wild-type TP53, age ≤65 years or without complex karyotype (CK) had relatively favorable outcomes in the del(17p) group. Furthermore, patients with del(17p) as a minor clone showed survival advantage compared with those with del(17p) as a major clone. These data suggest that the percentage of cells with del(17p), the size of the del(17p) subclone, CLL International Prognostic Index, and CK should be considered to build refined prognostication models for patients with TP53 disruption.

Agathangelidis A, Rosenquist R, Davi F, et al.
Immunoglobulin Gene Analysis in Chronic Lymphocytic Leukemia.
Methods Mol Biol. 2019; 1881:51-62 [PubMed] Related Publications
The formation of B-cell receptor immunoglobulin (BcR IG) is the result of a multi-step process that starts at the pro-B cell stage with the VDJ gene recombination of IG genes of the heavy chain, followed by VJ recombination of the light chain genes at the pre-B II cell stage. As a result, a fully functional BcR IG is expressed on the surface of any given naive B cell. After antigen encounter, somatic hypermutation (SHM) and class-switch recombination (CSR) act on the rearranged IG genes within the context of affinity maturation, leading to the expression of a BcR IG with unique immunogenetic and functional characteristics. Since B-cell neoplasms arise from the transformation of a single B cell, this renders IG gene rearrangements ideal clonal markers as they will be identical in all neoplastic cells of each individual clone. Furthermore, the rearranged IG sequence can also serve as a cell development/maturation marker, given that its configuration is tightly linked to specific B-cell developmental stages. Finally, in certain instances, as in the case of chronic lymphocytic leukemia (CLL), the clonotypic IG sequence and, more specifically, the load of somatic hypermutations within the rearranged IG heavy variable (IGHV) gene, holds prognostic and potentially predictive value. However, in order to take full advantage of the information provided from the analysis of the clonotypic IG gene rearrangement sequences, robust methods and tools need to be applied. Here, we provide details regarding the methodologies necessary to ensure reliable IG sequence analysis based on the recognized expertise of the European Research initiative on CLL (ERIC). All methodological and analytical steps are described below, starting from the isolation of blood mononuclear cells (PBMC), moving to the identification of the clonotypic IG rearrangement and ending with the accurate interpretation of the SHM status.

Yang YQ, Tian T, Zhu HY, et al.
NDRG2 mRNA levels and miR-28-5p and miR-650 activity in chronic lymphocytic leukemia.
BMC Cancer. 2018; 18(1):1009 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: NDRG2 is identified as a tumor suppressor gene in many tumors, and functions in cell proliferation, differentiation and apoptosis. Recent data indicate that NDRG2 expression is up-regulated by TP53. Moreover, proposed mechanisms of NDRG2 inactivation include epigenetic silencing of the NDRG2 promoter and down-regulation by microRNAs (miRNAs). However, few studies have ever been done on the role of NDRG2 and the NDRG2-regulating miRNAs interference in chronic lymphocytic leukemia (CLL).
METHODS: NDRG2 and microRNAs mRNA levels in CLL subjects were assessed by quantitative real-time polymerase chain reaction (qRT-PCR). The dual-luciferase reporter assay was performed to determine NDRG2-related miRNAs. Low expression of mature exogenous miRNAs in CLL cells was established by transient transfection. NDRG2 protein levels in CLL cells were detected by western blot. In addition, flow cytometry was conducted to examine the apoptosis of CLL cells.
RESULTS: Lower expression of NDRG2 was found in the B-cells from 102 CLL patients compared the 40 normal subjects (P < 0.001). Patients with advanced Binet stage (P = 0.001), high lactate dehydrogenase (LDH) level (P = 0.036), un-mutated immunoglobulin heavy chain variable region gene (IGHV) (P = 0.004) and those with p53 aberrations (P < 0.001) had a markedly lower levels of NDRG2 mRNA. This decrease was associated with briefer time-to-treatment (P = 0.001) and poorer survival (P < 0.001). High expression of miR-28-5p and miR-650 was associated with Binet B/C stage (P = 0.044) and IGHV un-mutated (P = 0.011), as well as Binet B/C stage (P = 0.013) and p53 aberrations (P = 0.037), respectively. Inhibition of miR-28-5p or miR-650 could induce more apoptosis in CLL cells with germline TP53.
CONCLUSIONS: NDRG2 mRNA levels might be a useful prognostic variable for patients of CLL and up-regulating NDRG2 transcription may be a therapy approach in CLL without p53 aberrations.

Rani L, Gogia A, Singh V, et al.
Comparative assessment of prognostic models in chronic lymphocytic leukemia: evaluation in Indian cohort.
Ann Hematol. 2019; 98(2):437-443 [PubMed] Related Publications
Prognostic indices combining several clinical and laboratory parameters have been proposed for prognostication in chronic lymphocytic leukemia (CLL). Recently, international consortium on CLL proposed an international prognostic index (CLL-IPI) integrating clinical, molecular, and genetic parameters. The present study was designed to evaluate the reproducibility of CLL-IPI in Indian CLL cohort. The prognostic ability of CLL-IPI in terms of overall survival (OS) and time to first treatment (TTFT) was investigated in treatment-naive CLL patients and also compared with other existing prognostic scores. For assigning scores, clinical and laboratory details were obtained from medical records, and IGHV gene mutation status, β2-microglobulin levels, and copy number variations were determined using c-DNA, ELISA, and multiplex ligation-dependent probe amplification (MLPA), respectively. The scores were generated as per the weighted grades assigned to each variable involved in score categorization. The predictive value of prognostic models was assessed and compared using Harrell's C-index and Akaike's information criterion (AIC). Stratification of patients according to CLL-IPI yielded significant differences in terms of OS and TTFT (p < 0.001). Comparative assessment of scores for OS suggested better performance of CLL-IPI (C = 0.64, AIC = 740) followed by Barcelona-Brno (C = 0.61, AIC = 754) and MDACC score (C = 0.59, AIC = 759). Comparison of predictive value of prognostic scores for TTFT illustrated better performance of CLL-IPI (C = 0.72, AIC = 726) followed by Barcelona-Brno (C = 0.68, AIC = 743), modified GCLLSG (C = 0.66, AIC = 744), and O-CLL1 index (C = 0.55, AIC = 773). The results suggest better performance of CLL-IPI in terms of both OS and TTFT as compared to other available scores in our cohort.

Xu L, Song JC, Sun XH, et al.
Richter's syndrome of the central nervous system diagnosed concurrently with chronic lymphocytic leukaemia: A case report and literature review.
Medicine (Baltimore). 2018; 97(41):e12701 [PubMed] Free Access to Full Article Related Publications
RATIONALE: Central nervous system (CNS) infiltration of Richter's syndrome (RS) is rare and only a few cases were discussed. Of these published cases, either they were accompanied with lymph node involvement or with a history of chronic lymphocytic leukemia (CLL). To our knowledge, this is the first published case of RS of the brain and meninges diagnosed concurrently with CLL in the absence of any evidence of lymphoma outside of the CNS.
PATIENT CONCERNS: A 67-year-old female presented with slurred speech, headache, and left-sided hemiparesis. Magnetic resonance imaging of the brain revealed an irregular lesion 30 mm in diameter in the right parietal lobe. The mass was totally removed and pathology revealed diffuse large B-cell lymphoma (DLBCL) of non-germinal center type by Hans' classification. The patient's leukocyte count was 12.1 × 109/L (76.9% lymphocytes), and fluorescence-activated cell sorting (FACS) analysis of blood revealed a clonal B-cell population (36.75% leukocytes) corresponding to the immunological CLL profile (Matutes score of 5/5). Bone marrow (BM) aspiration and biopsy also indicated CLL. The analysis of immunoglobulin heavy chain gene (IGH) and kappa chain gene (IGK) in the patient's BM and CNS tissue indicated that the DLBCL of the brain was derived from the CLL clone.
DIAGNOSES: RS of the CNS diagnosed concurrently with CLL.
INTERVENTIONS: The patient received intravenous chemotherapy (6.0 g methotrexate) and intrathecal chemotherapy (10 mg methotrexate, 50 mg cytarabine, 5 mg dexamethasone).
OUTCOMES: The patient returned to our department with left-sided hemiparesis and headache 2 weeks after the chemotherapy. Repeat MRI showed progression of the brain lesion. Her general condition deteriorated significantly with confusion and high fever, and she died within a few days at only 10 weeks after the onset of symptoms.
LESSONS: The survival of CNS-RS patients is very poor and and is always complicated with multiple and different genetic alterations. Because of chemotherapy insensitivity, a multidisciplinary treatment including surgery and radiotherapy together with novel agents may be an option to improving patient outcomes.

Herviou L, Kassambara A, Boireau S, et al.
PRC2 targeting is a therapeutic strategy for EZ score defined high-risk multiple myeloma patients and overcome resistance to IMiDs.
Clin Epigenetics. 2018; 10(1):121 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Multiple myeloma (MM) is a malignant plasma cell disease with a poor survival, characterized by the accumulation of myeloma cells (MMCs) within the bone marrow. Epigenetic modifications in MM are associated not only with cancer development and progression, but also with drug resistance.
METHODS: We identified a significant upregulation of the polycomb repressive complex 2 (PRC2) core genes in MM cells in association with proliferation. We used EPZ-6438, a specific small molecule inhibitor of EZH2 methyltransferase activity, to evaluate its effects on MM cells phenotype and gene expression prolile.
RESULTS: PRC2 targeting results in growth inhibition due to cell cycle arrest and apoptosis together with polycomb, DNA methylation, TP53, and RB1 target genes induction. Resistance to EZH2 inhibitor is mediated by DNA methylation of PRC2 target genes. We also demonstrate a synergistic effect of EPZ-6438 and lenalidomide, a conventional drug used for MM treatment, activating B cell transcription factors and tumor suppressor gene expression in concert with MYC repression. We establish a gene expression-based EZ score allowing to identify poor prognosis patients that could benefit from EZH2 inhibitor treatment.
CONCLUSIONS: These data suggest that PRC2 targeting in association with IMiDs could have a therapeutic interest in MM patients characterized by high EZ score values, reactivating B cell transcription factors, and tumor suppressor genes.

Abramenko IV, Bilous NI, Chumak AA, et al.
Analysis of the 3'UTR region of the NOTCH1 gene in chronic lymphocytic leukemia patients.
Exp Oncol. 2018; 40(3):211-217 [PubMed] Related Publications
Deregulation of NOTCH1-signalling pathway is common in chronic lymphocytic leukemia (CLL). The most of studies are focused on detection of the hotspot c.7541_7542delCT NOTCH1 mutations in exon 34, while studies of mutations in the 3'UTR region are rare. The aims of work were to evaluate the frequencies of mutations in the 3'UTR region of the NOTCH1 gene (9:136,495553-136,495994) in Ukrainian CLL patients, the distribution of rs3124591 genotypes located in that area, and association of NOTCH1 mutations with structure of B-cell receptor.
MATERIALS AND METHODS: Detection of mutations in the 3'UTR region of the NOTCH1 was performed by direct sequencing in 87 previously untreated CLL patients (from the total group of 237 CLL patients) with unmutated immunoglobulin heavy-chain variable (UM IGHV) genes and without mutations in hotspot regions of TP53, SF3B1, and exon 34 of NOTCH1 genes.
RESULTS: Mutations in the 3'UTR region of the NOTCH1 were revealed in three of 87 CLL patients (3.4%). Two cases with non-coding mutations were related to subset #1 of stereotyped B-cell receptors, and one case belonged to stereotyped subset #28a. Analysis with inclusion of 30 UM IGHV cases with previously detected c.7544_7545delCT mutations revealed that the frequency of UM IGHV genes of I phylogenetic clan (except IGHV1-69) was significantly increased, and the frequency of UM IGHV3 and IGHV4 genes, on the contrary, was reduced in NOTCH1-mutated cases comparing with NOTCH1-unmutated cases (p = 0.002) and the general group (p = 0.013). SNP rs3124591 did not affect the risk of CLL and survival parameters of the patients. At the same time, differences were found in the frequency of IGHV gene usage and in the structure of HCDR3 in carriers of individual genotypes.
CONCLUSION: The frequency of NOTCH1 mutations in 3'UTR region was low. Our findings confirmed current data on the association between the structure of the B-cell receptor and the appearance of NOTCH1 mutations. Some features of HCDR3 structure were identified in carriers of TT and CC genotypes of rs3124591.

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