Gene Summary

Gene:GALE; UDP-galactose-4-epimerase
Aliases: SDR1E1
Summary:This gene encodes UDP-galactose-4-epimerase which catalyzes two distinct but analogous reactions: the epimerization of UDP-glucose to UDP-galactose, and the epimerization of UDP-N-acetylglucosamine to UDP-N-acetylgalactosamine. The bifunctional nature of the enzyme has the important metabolic consequence that mutant cells (or individuals) are dependent not only on exogenous galactose, but also on exogenous N-acetylgalactosamine as a necessary precursor for the synthesis of glycoproteins and glycolipids. Mutations in this gene result in epimerase-deficiency galactosemia, also referred to as galactosemia type 3, a disease characterized by liver damage, early-onset cataracts, deafness and cognitive disability, with symptoms ranging from mild ('peripheral' form) to severe ('generalized' form). Multiple alternatively spliced transcripts encoding the same protein have been identified. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:UDP-glucose 4-epimerase
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 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 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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

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

Latest Publications: GALE (cancer-related)

Gao WZ, Guo LM, Xu TQ, et al.
Identification of a multidimensional transcriptome signature for survival prediction of postoperative glioblastoma multiforme patients.
J Transl Med. 2018; 16(1):368 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Glioblastoma multiform (GBM) is a devastating brain tumor with maximum surgical resection, radiotherapy plus concomitant and adjuvant temozolomide (TMZ) as the standard treatment. Diverse clinicopathological and molecular features are major obstacles to accurate predict survival and evaluate the efficacy of chemotherapy or radiotherapy. Reliable prognostic biomarkers are urgently needed for postoperative GBM patients.
METHODS: The protein coding genes (PCGs) and long non-coding RNA (lncRNA) gene expression profiles of 233 GBM postoperative patients were obtained from The Cancer Genome Atlas (TCGA), TANRIC and Gene Expression Omnibus (GEO) database. We randomly divided the TCGA set into a training (n = 76) and a test set (n = 77) and used GSE7696 (n = 80) as an independent validation set. Survival analysis and the random survival forest algorithm were performed to screen survival associated signature.
RESULTS: Six PCGs (EIF2AK3, EPRS, GALE, GUCY2C, MTHFD2, RNF212) and five lncRNAs (CTD-2140B24.6, LINC02015, AC068888.1, CERNA1, LINC00618) were screened out by a risk score model and formed a PCG-lncRNA signature for its predictive power was strongest (AUC = 0.78 in the training dataset). The PCG-lncRNA signature could divide patients into high- risk or low-risk group with significantly different survival (median 7.47 vs. 18.27 months, log-rank test P < 0.001) in the training dataset. Similar result was observed in the test dataset (median 11.40 vs. 16.80 months, log-rank test P = 0.001) and the independent set (median 8.93 vs. 16.22 months, log-rank test P = 0.007). Multivariable Cox regression analysis verified that it was an independent prognostic factor for the postsurgical patients with GBM. Compared with IDH mutation status, O-(6)-methylguanine DNA methyltransferase promoter methylation status and age, the signature was proved to have a superior predictive power. And stratified analysis found that the signature could further separated postoperative GBM patients who received TMZ-chemoradiation into high- and low-risk groups in TCGA and GEO dataset.
CONCLUSIONS: The PCG-lncRNA signature was a novel prognostic marker to predict survival and TMZ-chemoradiation response in GBM patients after surgery.

Whitworth J, Smith PS, Martin JE, et al.
Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.
Am J Hum Genet. 2018; 103(1):3-18 [PubMed] Free Access to Full Article Related Publications
Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ

Kumar AJ, Kim S, Hemmer MT, et al.
Graft-versus-host disease in recipients of male unrelated donor compared with parous female sibling donor transplants.
Blood Adv. 2018; 2(9):1022-1031 [PubMed] Free Access to Full Article Related Publications
Optimal donor selection is critical for successful allogeneic hematopoietic cell transplantation (HCT). Donor sex and parity are well-established risk factors for graft-versus-host disease (GVHD), with male donors typically associated with lower rates of GVHD. Well-matched unrelated donors (URDs) have also been associated with increased risks of GVHD as compared with matched sibling donors. These observations raise the question of whether male URDs would lead to more (or less) favorable transplant outcomes as compared with parous female sibling donors. We used the Center for International Blood and Marrow Transplant Research registry to complete a retrospective cohort study in adults with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome, who underwent T-cell replete HCT from these 2 donor types (parous female sibling or male URD) between 2000 and 2012. Primary outcomes included grade 2 to 4 acute GVHD (aGVHD), chronic GVHD (cGVHD), and overall survival. Secondary outcomes included disease-free survival, transplant-related mortality, and relapse. In 2813 recipients, patients receiving male URD transplants (n = 1921) had 1.6 times higher risk of grade 2 to 4 aGVHD (

Furness CL, Mansur MB, Weston VJ, et al.
The subclonal complexity of STIL-TAL1+ T-cell acute lymphoblastic leukaemia.
Leukemia. 2018; 32(9):1984-1993 [PubMed] Free Access to Full Article Related Publications
Single-cell genetics were used to interrogate clonal complexity and the sequence of mutational events in STIL-TAL1+ T-ALL. Single-cell multicolour FISH was used to demonstrate that the earliest detectable leukaemia subclone contained the STIL-TAL1 fusion and copy number loss of 9p21.3 (CDKN2A/CDKN2B locus), with other copy number alterations including loss of PTEN occurring as secondary subclonal events. In three cases, multiplex qPCR and phylogenetic analysis were used to produce branching evolutionary trees recapitulating the snapshot history of T-ALL evolution in this leukaemia subtype, which confirmed that mutations in key T-ALL drivers, including NOTCH1 and PTEN, were subclonal and reiterative in distinct subclones. Xenografting confirmed that self-renewing or propagating cells were genetically diverse. These data suggest that the STIL-TAL1 fusion is a likely founder or truncal event. Therapies targeting the TAL1 auto-regulatory complex are worthy of further investigation in T-ALL.

Gale D, Lawson ARJ, Howarth K, et al.
Development of a highly sensitive liquid biopsy platform to detect clinically-relevant cancer mutations at low allele fractions in cell-free DNA.
PLoS One. 2018; 13(3):e0194630 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Detection and monitoring of circulating tumor DNA (ctDNA) is rapidly becoming a diagnostic, prognostic and predictive tool in cancer patient care. A growing number of gene targets have been identified as diagnostic or actionable, requiring the development of reliable technology that provides analysis of multiple genes in parallel. We have developed the InVision™ liquid biopsy platform which utilizes enhanced TAm-Seq™ (eTAm-Seq™) technology, an amplicon-based next generation sequencing method for the identification of clinically-relevant somatic alterations at low frequency in ctDNA across a panel of 35 cancer-related genes.
MATERIALS AND METHODS: We present analytical validation of the eTAm-Seq technology across two laboratories to determine the reproducibility of mutation identification. We assess the quantitative performance of eTAm-Seq technology for analysis of single nucleotide variants in clinically-relevant genes as compared to digital PCR (dPCR), using both established DNA standards and novel full-process control material.
RESULTS: The assay detected mutant alleles down to 0.02% AF, with high per-base specificity of 99.9997%. Across two laboratories, analysis of samples with optimal amount of DNA detected 94% mutations at 0.25%-0.33% allele fraction (AF), with 90% of mutations detected for samples with lower amounts of input DNA.
CONCLUSIONS: These studies demonstrate that eTAm-Seq technology is a robust and reproducible technology for the identification and quantification of somatic mutations in circulating tumor DNA, and support its use in clinical applications for precision medicine.

Plagnol V, Woodhouse S, Howarth K, et al.
Analytical validation of a next generation sequencing liquid biopsy assay for high sensitivity broad molecular profiling.
PLoS One. 2018; 13(3):e0193802 [PubMed] Free Access to Full Article Related Publications
Circulating tumor DNA (ctDNA) analysis is being incorporated into cancer care; notably in profiling patients to guide treatment decisions. Responses to targeted therapies have been observed in patients with actionable mutations detected in plasma DNA at variant allele fractions (VAFs) below 0.5%. Highly sensitive methods are therefore required for optimal clinical use. To enable objective assessment of assay performance, detailed analytical validation is required. We developed the InVisionFirst™ assay, an assay based on enhanced tagged amplicon sequencing (eTAm-Seq™) technology to profile 36 genes commonly mutated in non-small cell lung cancer (NSCLC) and other cancer types for actionable genomic alterations in cell-free DNA. The assay has been developed to detect point mutations, indels, amplifications and gene fusions that commonly occur in NSCLC. For analytical validation, two 10mL blood tubes were collected from NSCLC patients and healthy volunteer donors. In addition, contrived samples were used to represent a wide spectrum of genetic aberrations and VAFs. Samples were analyzed by multiple operators, at different times and using different reagent Lots. Results were compared with digital PCR (dPCR). The InVisionFirst assay demonstrated an excellent limit of detection, with 99.48% sensitivity for SNVs present at VAF range 0.25%-0.33%, 92.46% sensitivity for indels at 0.25% VAF and a high rate of detection at lower frequencies while retaining high specificity (99.9997% per base). The assay also detected ALK and ROS1 gene fusions, and DNA amplifications in ERBB2, FGFR1, MET and EGFR with high sensitivity and specificity. Comparison between the InVisionFirst assay and dPCR in a series of cancer patients showed high concordance. This analytical validation demonstrated that the InVisionFirst assay is highly sensitive, specific and robust, and meets analytical requirements for clinical applications.

Farmery JHR, Smith ML,
Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data.
Sci Rep. 2018; 8(1):1300 [PubMed] Free Access to Full Article Related Publications
Telomere length is a risk factor in disease and the dynamics of telomere length are crucial to our understanding of cell replication and vitality. The proliferation of whole genome sequencing represents an unprecedented opportunity to glean new insights into telomere biology on a previously unimaginable scale. To this end, a number of approaches for estimating telomere length from whole-genome sequencing data have been proposed. Here we present Telomerecat, a novel approach to the estimation of telomere length. Previous methods have been dependent on the number of telomeres present in a cell being known, which may be problematic when analysing aneuploid cancer data and non-human samples. Telomerecat is designed to be agnostic to the number of telomeres present, making it suited for the purpose of estimating telomere length in cancer studies. Telomerecat also accounts for interstitial telomeric reads and presents a novel approach to dealing with sequencing errors. We show that Telomerecat performs well at telomere length estimation when compared to leading experimental and computational methods. Furthermore, we show that it detects expected patterns in longitudinal data, repeated measurements, and cross-species comparisons. We also apply the method to a cancer cell data, uncovering an interesting relationship with the underlying telomerase genotype.

Qayed M, Wang T, Hemmer MT, et al.
Influence of Age on Acute and Chronic GVHD in Children Undergoing HLA-Identical Sibling Bone Marrow Transplantation for Acute Leukemia: Implications for Prophylaxis.
Biol Blood Marrow Transplant. 2018; 24(3):521-528 [PubMed] Free Access to Full Article Related Publications
Relapse remains the major cause of mortality after hematopoietic cell transplantation (HCT) for pediatric acute leukemia. Previous research has suggested that reducing the intensity of calcineurin inhibitor-based graft-versus-host disease (GVHD) prophylaxis may be an effective strategy for abrogating the risk of relapse in pediatric patients undergoing matched sibling donor (MSD) HCT. We reasoned that the benefits of this strategy could be maximized by selectively applying it to those patients least likely to develop GVHD. We conducted a study of risk factors for GVHD, to risk-stratify patients based on age. Patients age <18 years with leukemia who received myeloablative, T cell-replete MSD bone marrow transplantation and calcineurin inhibitor-based GVHD prophylaxis between 2000 and 2013 and were entered into the Center for International Blood and Marrow Transplant Research registry were included. The cumulative incidence of grade II-IV acute GVHD (aGVHD) was 19%, that of grade II-IV aGVHD 7%, and that of chronic GVHD (cGVHD) was 16%. Compared with age 13 to 18 years, age 2 to 12 years was associated with a lower risk of grade II-IV aGVHD (hazard ratio [HR], .42; 95% confidence interval [CI], .26 to .70; P = .0008), grade II-IV aGVHD (HR, .24; 95% CI, .10 to .56; P = .001), and cGVHD (HR, .32; 95% CI, .19 to .54; P < .001). Compared with 2000-2004, the risk of grade II-IV aGVHD was lower in children undergoing transplantation in 2005-2008 (HR, .36; 95% CI, .20 to .65; P = .0007) and in 2009-2013 (HR, .24; 95% CI. .11 to .53; P = .0004). Similarly, the risk of grade III-IV aGVHD was lower in children undergoing transplantation in 2005-2008 (HR, .23; 95% CI, .08 to .65; P = .0056) and 2009-2013 (HR, .16; 95% CI, .04 to .67; P = .0126) compared with those doing so in 2000-2004. We conclude that aGVHD rates have decreased significantly over time, and that children age 2 to 12 years are at very low risk for aGVHD and cGVHD. These results should be validated in an independent analysis, because these patients with high-risk malignancies may be good candidates for trials of reduced GVHD prophylaxis.

El-Sharkawi D, Sproul D, Allen CG, et al.
Variable outcome and methylation status according to
Haematologica. 2018; 103(1):91-100 [PubMed] Free Access to Full Article Related Publications

Chan MMY, Barnicoat A, Mumtaz F, et al.
Cascade Fumarate Hydratase mutation screening allows early detection of kidney tumour: a case report.
BMC Med Genet. 2017; 18(1):79 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Fumarate hydratase (FH) deficiency is a rare autosomal recessive disorder which results in a major defect in cellular metabolism. It presents in infancy with progressive encephalopathy, hypotonia, seizures and failure to thrive and is often fatal in childhood. It is caused by mutations in the FH gene (1q42.1) that result in deficiency of the citric acid cycle enzyme fumarate hydratase, resulting in accumulation of fumaric acid. Heterozygous germline mutations in the FH gene predispose to an aggressive autosomal dominant inherited early-onset kidney cancer syndrome: hereditary leiomyomatosis and renal cell cancer (HLRCC).
CASE PRESENTATION: Cascade FH mutation screening enabled the early diagnosis of a renal tumour in an asymptomatic parent of a child with fumarate hydratase deficiency, resulting in timely and possibly life-saving treatment.
CONCLUSION: While the theoretical risk of kidney cancer in parents of children with recessive fumarate hydratase deficiency is well recognized, to our knowledge this is the first report of a kidney tumour being detected in a parent by screening performed for this indication. This underscores the importance of offering lifelong kidney surveillance to such parents and other heterozygous relatives of children born with fumarate hydratase deficiency.

Li B, Gale RP, Xu Z, et al.
Non-driver mutations in myeloproliferative neoplasm-associated myelofibrosis.
J Hematol Oncol. 2017; 10(1):99 [PubMed] Free Access to Full Article Related Publications
We studied non-driver mutations in 62 subjects with myeloproliferative neoplasm (MPN)-associated myelofibrosis upon diagnosis, including 45 subjects with primary myelofibrosis (PMF) and 17 with post-polycythemia vera or post-essential thrombocythemia myelofibrosis (post-PV/ET MF). Fifty-eight subjects had ≥1 non-driver mutation upon diagnosis. Mutations in mRNA splicing genes, especially in U2AF1, were significantly more frequent in PMF than in post-PV/ET MF (33 vs. 6%; P = 0.015). There were also striking differences in clonal architecture. These data indicate different genomic spectrums between PMF and post-PV/ET MF.

Vrooman LM, Millard HR, Brazauskas R, et al.
Survival and Late Effects after Allogeneic Hematopoietic Cell Transplantation for Hematologic Malignancy at Less than Three Years of Age.
Biol Blood Marrow Transplant. 2017; 23(8):1327-1334 [PubMed] Free Access to Full Article Related Publications
Very young children undergoing hematopoietic cell transplantation (HCT) are a unique and vulnerable population. We analyzed outcomes of 717 patients from 117 centers who survived relapse free for ≥1 year after allogeneic myeloablative HCT for hematologic malignancy at <3 years of age, between 1987 and 2012. The median follow-up was 8.3 years (range, 1.0 to 26.4 years); median age at follow-up was 9 years (range, 2 to 29 years). Ten-year overall and relapse-free survival were 87% (95% confidence interval [CI], 85% to 90%) and 84% (95% CI, 81% to 87%). Ten-year cumulative incidence of relapse was 11% (95% CI, 9% to 13%). Of 84 deaths, relapse was the leading cause (43%). Chronic graft-versus-host-disease 1 year after HCT was associated with increased risk of mortality (hazard ratio [HR], 2.1; 95% CI, 1.3 to 3.3; P = .0018). Thirty percent of patients experienced ≥1 organ toxicity/late effect >1 year after HCT. The most frequent late effects included growth hormone deficiency/growth disturbance (10-year cumulative incidence, 23%; 95% CI, 19% to 28%), cataracts (18%; 95% CI, 15% to 22%), hypothyroidism (13%; 95% CI, 10% to 16%), gonadal dysfunction/infertility requiring hormone replacement (3%; 95% CI, 2% to 5%), and stroke/seizure (3%; 95% CI, 2% to 5%). Subsequent malignancy was reported in 3.6%. In multivariable analysis, total body irradiation (TBI) was predictive of increased risk of cataracts (HR, 17.2; 95% CI, 7.4 to 39.8; P < .001), growth deficiency (HR, 3.5; 95% CI, 2.2 to 5.5; P < .001), and hypothyroidism (HR, 5.3; 95% CI, 3.0 to 9.4; P < .001). In summary, those who survived relapse free ≥1 year after HCT for hematologic malignancy at <3 years of age had favorable overall survival. Chronic graft-versus-host-disease and TBI were associated with adverse outcomes. Future efforts should focus on reducing the risk of relapse and late effects after HCT at early age.

Wang SJ, Wang PZ, Gale RP, et al.
Cysteine and glycine-rich protein 2 (CSRP2) transcript levels correlate with leukemia relapse and leukemia-free survival in adults with B-cell acute lymphoblastic leukemia and normal cytogenetics.
Oncotarget. 2017; 8(22):35984-36000 [PubMed] Free Access to Full Article Related Publications
Relapse is the major cause of treatment-failure in adults with B-cell acute lymphoblastic leukemia (ALL) achieving complete remission after induction chemotherapy. Greater precision identifying persons likely to relapse is important. We did bio-informatics analyses of transcriptomic data to identify mRNA transcripts aberrantly-expressed in B-cell ALL. We selected 9 candidate genes for validation 7 of which proved significantly-associated with B-cell ALL. We next focused on function and clinical correlations of the cysteine and glycine-rich protein 2 (CSRP2). Quantitative real-time polymerase chain reaction (RT-qPCR) was used to examine gene transcript levels in bone marrow samples from 236 adults with B-cell ALL compared with samples from normals. CSRP2 was over-expressed in 228 out of 236 adults (97%) with newly-diagnosed B-cell ALL. A prognostic value was assessed in 168 subjects. In subjects with normal cytogenetics those with high CSRP2 transcript levels had a higher 5-year cumulative incidence of relapse (CIR) and worse relapse-free survival (RFS) compared with subjects with low transcript levels (56% [95% confidence interval, 53, 59%] vs. 19% [18, 20%]; P = 0.011 and 41% [17, 65%] vs. 80% [66-95%]; P = 0.007). In multivariate analyses a high CSRP2 transcript level was independently-associated with CIR (HR = 5.32 [1.64-17.28]; P = 0.005) and RFS (HR = 5.56 [1.87, 16.53]; P = 0.002). Functional analyses indicated CSRP2 promoted cell proliferation, cell-cycle progression, in vitro colony formation and cell migration ability. Abnormal CSRP2 expression was associated with resistance to chemotherapy; sensitivity was restored by down-regulating CSRP2 expression.

Li D, Gale RP, Liu Y, et al.
5'-Triphosphate siRNA targeting MDR1 reverses multi-drug resistance and activates RIG-I-induced immune-stimulatory and apoptotic effects against human myeloid leukaemia cells.
Leuk Res. 2017; 58:23-30 [PubMed] Related Publications
Multi-drug resistance (MDR), immune suppression and decreased apoptosis are important causes of therapy-failure in leukaemia. Short interfering RNAs (siRNAs) down-regulate gene transcription, have sequence-independent immune-stimulatory effects and synergize with other anti-cancer therapies in some experimental models. We designed a siRNA targeting MDR1 with 5'-triphosphate ends (3p-siRNA-MDR1). Treatment of leukaemia cells with 3p-siRNA-MDR1 down-regulated MDR1 expression, reduced-drug resistance and induced immune and pro-apoptotic effects in drug-resistant HL-60/Adr and K562/Adr human leukaemia cell lines. We show mechanisms-of-action of these effects involve alterations in the anti-viral cytosolic retinoic acid-inducible protein-I (RIG-I; encoded by RIG-I or DDX58) mediated type-I interferon signal induction, interferon-gamma-inducible protein 10 (IP-10; encoded by IP10 or CXCL10) secretion, major histocompatibility complex-I expression (MHC-I) and caspase-mediated cell apoptosis. 3p-siRNA-MDR1 transfection also enhanced the anti-leukaemia efficacy of doxorubicin. These data suggest a possible synergistic role for 3p-siRNA-MDR1 in anti-leukaemia therapy.

Khoury HJ, Wang T, Hemmer MT, et al.
Improved survival after acute graft-
Haematologica. 2017; 102(5):958-966 [PubMed] Free Access to Full Article Related Publications
A cute graft-

Rahman S, Magnussen M, León TE, et al.
Activation of the
Blood. 2017; 129(24):3221-3226 [PubMed] Free Access to Full Article Related Publications
Somatic mutations within noncoding genomic regions that aberrantly activate oncogenes have remained poorly characterized. Here we describe recurrent activating intronic mutations of

Ge Z, Gu Y, Han Q, et al.
Targeting High Dynamin-2 (DNM2) Expression by Restoring Ikaros Function in Acute Lymphoblastic Leukemia.
Sci Rep. 2016; 6:38004 [PubMed] Free Access to Full Article Related Publications
Dynamin-2 (DNM2) is a GTPase essential for intracellular vesicle formation and trafficking, cytokinesis and receptor endocytosis. Mutations in DNM2 are common in early T-cell precursor acute lymphoblastic leukemia. However, DNM2 expression in other types of ALL are not reported. We studied DNM2 mRNA level in adults with B- and T-cell ALL. We found DNM2 is more highly expressed compared with normals in both forms of ALL. High DNM2 expression is associated with some clinical and laboratory features, inferior outcomes and with leukaemia cell proliferation. We also found Ikaros directly binds the DNM2 promoter and suppresses DNM2 expression. Consequently IKZF1 deletion is associated with high DNM2 expression. Conversely, casein kinase-2 (CK2)-inhibitor increases Ikaros function thereby inhibiting DNM2 expression. Inhibiting DNM2 suppresses proliferation of leukemia cells and synergizes with CK2 inhibition. Our data indicate high DNM2 expression is associated with Ikaros dysregulation and may be important in the development of B-ALL.

Cornell RF, D'Souza A, Kassim AA, et al.
Maintenance versus Induction Therapy Choice on Outcomes after Autologous Transplantation for Multiple Myeloma.
Biol Blood Marrow Transplant. 2017; 23(2):269-277 [PubMed] Free Access to Full Article Related Publications
Bortezomib (V), lenalidomide (R), cyclophosphamide (C), and dexamethasone (D) are components of the most commonly used modern doublet (RD, VD) or triplet (VRD, CVD) initial induction regimens before autologous hematopoietic cell transplantation (AHCT) for multiple myeloma (MM) in the United States. In this study we evaluated 693 patients receiving "upfront" AHCT after initial induction therapy with modern doublet or triplet regimens using data reported to the Center for International Blood and Marrow Transplant Research from 2008 to 2013. Analysis was limited to those receiving a single AHCT after 1 line of induction therapy within 12 months from treatment initiation for MM. In multivariate analysis, progression-free survival (PFS) and overall survival were similar irrespective of induction regimen. However, high-risk cytogenetics and nonreceipt of post-transplant maintenance/consolidation therapy were associated with higher risk of relapse. Patients receiving post-transplant therapy had significantly improved 3-year PFS versus no post-transplant therapy (55% versus 39%, P = .0001). This benefit was most evident in patients not achieving at least a complete response post-AHCT (P = .005). In patients receiving upfront AHCT, the choice of induction regimen (doublet or triplet therapies) appears to be of lower impact than use of post-transplant therapy.

Mayfield JR, Czuchlewski DR, Gale JM, et al.
Integration of ruxolitinib into dose-intensified therapy targeted against a novel JAK2 F694L mutation in B-precursor acute lymphoblastic leukemia.
Pediatr Blood Cancer. 2017; 64(5) [PubMed] Free Access to Full Article Related Publications
A 17-year-old girl with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with persistent minimal residual disease (MRD) who underwent standard chemotherapy was found to have a BCR-ABL1-like gene expression pattern. Genome sequencing revealed a JAK2 mutation not previously described in BCP-ALL and a potential therapeutic target. Due to concern for an on-therapy relapse, the JAK2 inhibitor ruxolitinib was incorporated into a modified chemotherapy backbone to achieve complete remission prior to stem cell transplant. Treatment was well tolerated and she had undetectable MRD prior to a matched allogeneic stem cell transplant and remained in remission at day +100.

Cornell RF, Bachanova V, D'Souza A, et al.
Allogeneic Transplantation for Relapsed Waldenström Macroglobulinemia and Lymphoplasmacytic Lymphoma.
Biol Blood Marrow Transplant. 2017; 23(1):60-66 [PubMed] Free Access to Full Article Related Publications
Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) is characterized by lymphoplasmacytic proliferation, lymph node and spleen enlargement, bone marrow involvement, and IgM production. Treatment varies based on the extent and biology of disease. In some patients, the use of allogeneic hematopoietic cell transplantation (alloHCT) may have curative potential. We evaluated long-term outcomes of 144 patients who received adult alloHCT for WM/LPL. Data were obtained from the Center for International Blood and Marrow Transplant Research database (2001 to 2013). Patients received myeloablative(n = 67) or reduced-intensity conditioning (RIC; n = 67). Median age at alloHCT was 53 years, and median time from diagnosis to transplantation was 41 months. Thirteen percent (n = 18) failed prior autologous HCT. About half (n = 82, 57%) had chemosensitive disease at the time of transplantation, whereas 22% had progressive disease. Rates of progression-free survival, overall survival, relapse, and nonrelapse mortality at 5 years were 46%, 52%, 24%, and 30%, respectively. Patients with chemosensitive disease and better pretransplant disease status experienced significantly superior overall survival. There were no significant differences in progression-free survival based on conditioning (myeloablative, 50%, versus RIC, 41%) or graft source. Conditioning intensity did not impact treatment-related mortality or relapse. The most common causes of death were primary disease and graft-versus-host disease (GVHD). AlloHCT yielded durable survival in select patients with WM/LPL. Strategies to reduce mortality from GVHD and post-transplant relapse are necessary to improve this approach.

Stringaris K, Marin D, Barrett AJ, et al.
KIR gene haplotype: an independent predictor of clinical outcome in MDS patients.
Blood. 2016; 128(24):2819-2823 [PubMed] Free Access to Full Article Related Publications
Myelodysplastic syndromes (MDSs) are a group of hematopoietic disorders affecting the myeloid lineage, characterized by cytopenias and clonal evolution to acute myeloid leukemia (AML). We hypothesized that natural killer (NK) cells and their activating killer immunoglobulin-like receptors (aKIRs) influence the immune surveillance and clinical outcome of patients with MDSs. Here, we first examined the distribution of aKIR genes and haplotype in 2 independent cohorts of MDS and AML patients. The median number of aKIR genes was lower in MDS patients than healthy controls (2 vs 3 genes; P = .001), and lower in patients with secondary AML (progressed from MDSs) compared with de novo AML patients (2 vs 3; P = .008) and healthy controls (2 vs 3; P = .006). In a multivariate analysis, the presence of KIR haplotype A (characterized by low aKIR content 0-1) independently predicted a higher risk of conversion to AML (relative risk [RR] with 95% confidence interval [CI], 2.67 [1.13-6.71]; P = .02) and worse adjusted progression-free survival (RR with 95% CI, 2.96 [1.59-5.52]; P = .001) and overall survival (2.25 [1.17-4.31]; P = .02), compared with KIR haplotype B (multiple aKIR genes). These novel findings may help to identify MDS patients with a high risk of disease progression who would likely benefit from adoptive NK-cell therapy.

Ali A, Gale RE, Shakoori AR
Detection of FLT3/TKD and IDH1 Mutations in Pakistani Acute Myeloid Leukemia Patients by Denaturing HPLC.
J Cell Biochem. 2017; 118(5):1174-1181 [PubMed] Related Publications
Acute myeloid leukemia (AML) is characterized by an increase in the number of myeloid cells in the marrow and an arrest in their maturation. Various genetic mutations are associated with AML. FMS-like tyrosine kinase 3 (FLT3), a member of the class III receptor tyrosine kinase family, plays an important role in stem cell survival, and the development of dendritic and natural killer cells. FLT3/TKD mutations are generally missense mutations or in-frame alterations of residues D835 and I836 within the activation loop of the FLT3 protein. D835 mutations have been reported to occur in ≈ 7% of AML patients. Mutations have also been reported in exon 4 of isocitrate dehydrogenase 1 (IDH1) in ≈9% of AML patients. Mutations in FLT3/TKD and IDH1 genes were studied in AML patients from Pakistan and correlated with the laboratory findings. FLT3/TKD mutations were found in 7%, while IDH1 mutations were found in 10% Pakistani AML patients. Neither of these mutations was significantly correlated with age and sex, although the incidence of these mutations was higher in female patients. These mutations were found to be positively associated with each other. IDH1 mutations were positively associated with FAB type M1 and negatively associated with FAB type M2. In conclusion, the overall incidence of all these mutations in Pakistani patients was within the globally reported ranges. J. Cell. Biochem. 118: 1174-1181, 2017. © 2016 Wiley Periodicals, Inc.

Deol A, Sengsayadeth S, Ahn KW, et al.
Does FLT3 mutation impact survival after hematopoietic stem cell transplantation for acute myeloid leukemia? A Center for International Blood and Marrow Transplant Research (CIBMTR) analysis.
Cancer. 2016; 122(19):3005-3014 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Patients with FMS like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML) have a poor prognosis and are referred for early allogeneic hematopoietic stem cell transplantation (HCT).
METHODS: Data from the Center for International Blood and Marrow Transplant Research (CIBMTR) were used to evaluate 511 adult patients with de novo AML who underwent HCT during 2008 through 2011 to determine whether FLT3 mutations had an impact on HCT outcomes.
RESULTS: In total, 158 patients (31%) had FLT3 mutations. Univariate and multivariate analyses revealed an increased risk of relapse at 3 years in the FLT3 mutated group compared with the wild-type (WT) group (38% [95% confidence interval (CI), 30%-45%] vs 28% [95% CI, 24%-33%]; P = .04; relative risk, 1.60 [95% CI, 1.15-2.22]; P = .0048). However, FLT3 mutation status was not significantly associated with nonrelapse mortality, leukemia-free survival, or overall survival. Although more patients in the FLT3 mutated group died from relapsed primary disease compared with those in the WT group (60% vs 46%), the 3-year overall survival rate was comparable for the 2 groups (mutated group: 49%; 95% CI, 40%-57%; WT group: 55%, 95% CI, 50%-60%; P = .20).
CONCLUSIONS: The current data indicate that FLT3 mutation status did not adversely impact overall survival after HCT, and about 50% of patients with this mutation who underwent HCT were long-term survivors. Cancer 2016;122:3005-3014. © 2016 American Cancer Society.

Yin J, Zhang F, Tao H, et al.
BCL11A expression in acute phase chronic myeloid leukemia.
Leuk Res. 2016; 47:88-92 [PubMed] Related Publications
Chronic myeloid leukemia (CML) has chronic and acute phases. In chronic phase myeloid differentiation is preserved whereas in acute phase myeloid differentiation is blocked. Acute phase CML resembles acute myeloid leukemia (AML). Chronic phase CML is caused by BCR-ABL1. What additional mutation(s) cause transition to acute phase is unknown and may differ in different persons with CML. BCL11A encodes a transcription factor and is aberrantly-expressed in several haematological and solid neoplasms. We analyzed BCL11A mRNA levels in subjects with chronic and acute phase CML. BCL11A transcript levels were increased in subjects with CML in acute phase compared with those in normals and in subjects in chronic phase including some subjects studied in both phases. BCL11A mRNA levels were correlated with percent bone marrow blasts and significantly higher in lymphoid versus myeloid blast crisis. Differentiation of K562 with butyric acid, a CML cell line, decreased BCL11A mRNA levels. Cytology and flow cytometry analyses showed that ectopic expression of BCL11A in K562 cells blocked differentiation. These data suggest BCL11A may operate in transformation of CML from chronic to acute phase in some persons.

Qin YZ, Wang Y, Zhu HH, et al.
Low WT1 transcript levels at diagnosis predicted poor outcomes of acute myeloid leukemia patients with t(8;21) who received chemotherapy or allogeneic hematopoietic stem cell transplantation.
Chin J Cancer. 2016; 35:46 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Acute myeloid leukemia (AML) with t(8;21) is a heterogeneous disease. Identifying AML patients with t(8;21) who have a poor prognosis despite achieving remission is important for determining the best subsequent therapy. This study aimed to evaluate the impact of Wilm tumor gene-1 (WT1) transcript levels and cellular homolog of the viral oncogene v-KIT receptor tyrosine kinase (C-KIT) mutations at diagnosis, and RUNX1-RUNX1T1 transcript levels after the second consolidation chemotherapy cycle on outcomes.
METHODS: Eighty-eight AML patients with t(8;21) who received chemotherapy only or allogeneic hematopoietic stem cell transplantation (allo-HSCT) were included. Patients who achieved remission, received two or more cycles of consolidation chemotherapy, and had a positive measureable residual disease (MRD) test result (defined as <3-log reduction in RUNX1-RUNX1T1 transcript levels compared to baseline) after 2-8 cycles of consolidation chemotherapy were recommended to receive allo-HSCT. Patients who had a negative MRD test result were recommended to receive further chemotherapy up to only 8 cycles. WT1 transcript levels and C-KIT mutations at diagnosis, and RUNX1-RUNX1T1 transcript levels after the second consolidation chemotherapy cycle were tested.
RESULTS: Patients who had a C-KIT mutation had significantly lower WT1 transcript levels than patients who did not have a C-KIT mutation (6.7% ± 10.6% vs. 19.5% ± 19.9%, P < 0.001). Low WT1 transcript levels (≤5.0%) but not C-KIT mutation at diagnosis, a positive MRD test result after the second cycle of consolidation chemotherapy, and receiving only chemotherapy were independently associated with high cumulative incidence of relapse in all patients (hazard ratio [HR] = 3.53, 2.30, and 11.49; 95% confidence interval [CI] 1.64-7.62, 1.82-7.56, and 4.43-29.82; P = 0.002, 0.034, and <0.001, respectively); these conditions were also independently associated with low leukemia-free survival (HR = 3.71, 2.33, and 5.85; 95% CI 1.82-7.56, 1.17-4.64, and 2.75-12.44; P < 0.001, 0.016, and <0.001, respectively) and overall survival (HR = 3.50, 2.32, and 4.34; 95% CI 1.56-7.82, 1.09-4.97, and 1.98-9.53; P = 0.002, 0.030, and <0.001, respectively) in all patients.
CONCLUSIONS: Testing for WT1 transcript levels at diagnosis in patients with AML and t(8;21) may predict outcomes in those who achieve remission. A randomized study is warranted to determine whether allo-HSCT can improve prognosis in these patients.

Khwaja A, Bjorkholm M, Gale RE, et al.
Acute myeloid leukaemia.
Nat Rev Dis Primers. 2016; 2:16010 [PubMed] Related Publications
Acute myeloid leukaemia (AML) is a disorder characterized by a clonal proliferation derived from primitive haematopoietic stem cells or progenitor cells. Abnormal differentiation of myeloid cells results in a high level of immature malignant cells and fewer differentiated red blood cells, platelets and white blood cells. The disease occurs at all ages, but predominantly occurs in older people (>60 years of age). AML typically presents with a rapid onset of symptoms that are attributable to bone marrow failure and may be fatal within weeks or months when left untreated. The genomic landscape of AML has been determined and genetic instability is infrequent with a relatively small number of driver mutations. Mutations in genes involved in epigenetic regulation are common and are early events in leukaemogenesis. The subclassification of AML has been dependent on the morphology and cytogenetics of blood and bone marrow cells, but specific mutational analysis is now being incorporated. Improvements in treatment in younger patients over the past 35 years has largely been due to dose escalation and better supportive care. Allogeneic haematopoietic stem cell transplantation may be used to consolidate remission in those patients who are deemed to be at high risk of relapse. A plethora of new agents - including those targeted at specific biochemical pathways and immunotherapeutic approaches - are now in trial based on improved understanding of disease pathophysiology. These advances provide good grounds for optimism, although mortality remains high especially in older patients.

Sellar RS, Fraser L, Khwaja A, et al.
Cell cycle status in AML blast cells from peripheral blood, bone marrow aspirates and trephines and implications for biological studies and treatment.
Br J Haematol. 2016; 174(2):275-9 [PubMed] Related Publications
Using immunohistochemistry and flow cytometry to define phases of the cell cycle, this study shows that a high proportion of acute myeloid leukaemia (AML) blasts obtained from trephine biopsies are cycling, whereas >95% of peripheral blood-derived blasts are arrested in G1 . Results obtained from bone marrow aspirates are more similar to those from blood rather than from trephine biopsies. These differences were confirmed by gene expression profiling in a patient with high count AML. This has implications for cell cycle and other biological studies using aspirates rather than trephine biopsies and for the use of cell mobilising agents before chemotherapy.

Chaudhury S, Sparapani R, Hu ZH, et al.
Outcomes of Allogeneic Hematopoietic Cell Transplantation in Children and Young Adults with Chronic Myeloid Leukemia: A CIBMTR Cohort Analysis.
Biol Blood Marrow Transplant. 2016; 22(6):1056-1064 [PubMed] Free Access to Full Article Related Publications
Chronic myeloid leukemia (CML) in children and young adults is uncommon. Young patients have long life expectancies and low morbidity with hematopoietic cell transplantation (HCT). Prolonged tyrosine kinase inhibitor (TKI) use may cause significant morbidity. In addition, indication for HCT in patients in the first chronic phase is not established. We hence retrospectively evaluated outcomes in 449 CML patients with early disease receiving myeloablative HCT reported to the CIBMTR. We analyzed various factors affecting outcome, specifically the effect of age and pre-HCT TKI in pediatric patients (age < 18 years, n = 177) and young adults (age 18 to 29 years, n = 272) with the goal of identifying prognostic factors. Post-HCT probability rates of 5-year overall survival (OS) and leukemia-free survival (LFS) were 75% and 59%, respectively. Rates of OS and LFS were 76% and 57% in <18-year and 74% and 60% in 18- to 29-year group, respectively, by univariate analysis (P = .1 and = .6). Five-year rates of OS for HLA matched sibling donor (MSD) and bone marrow (BM) stem cell source were 83% and 80%, respectively. In multivariate analysis there was no effect of age (<18 versus 18 to 29) or pre-HCT TKI therapy on OS, LFS, transplant related mortality, or relapse. Favorable factors for OS were MSD (P < .001) and recent HCT (2003 to 2010; P = .04). LFS was superior with MSD (P < .001), BM as graft source (P = .001), and performance scores > 90 (P = .03) compared with unrelated or mismatched peripheral blood stem cells donors and recipients with lower performance scores. Older age was associated with increased incidence of chronic graft-versus-host disease (P = .0002). In the current era, HCT outcomes are similar in young patients and children with early CML, and best outcomes are achieved with BM grafts and MSD.

Saunders EJ, Dadaev T, Leongamornlert DA, et al.
Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array.
Br J Cancer. 2016; 114(8):945-52 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Germline mutations within DNA-repair genes are implicated in susceptibility to multiple forms of cancer. For prostate cancer (PrCa), rare mutations in BRCA2 and BRCA1 give rise to moderately elevated risk, whereas two of B100 common, low-penetrance PrCa susceptibility variants identified so far by genome-wide association studies implicate RAD51B and RAD23B.
METHODS: Genotype data from the iCOGS array were imputed to the 1000 genomes phase 3 reference panel for 21 780 PrCa cases and 21 727 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. We subsequently performed single variant, gene and pathway-level analyses using 81 303 SNPs within 20 Kb of a panel of 179 DNA-repair genes.
RESULTS: Single SNP analyses identified only the previously reported association with RAD51B. Gene-level analyses using the SKAT-C test from the SNP-set (Sequence) Kernel Association Test (SKAT) identified a significant association with PrCa for MSH5. Pathway-level analyses suggested a possible role for the translesion synthesis pathway in PrCa risk and Homologous recombination/Fanconi Anaemia pathway for PrCa aggressiveness, even though after adjustment for multiple testing these did not remain significant.
CONCLUSIONS: MSH5 is a novel candidate gene warranting additional follow-up as a prospective PrCa-risk locus. MSH5 has previously been reported as a pleiotropic susceptibility locus for lung, colorectal and serous ovarian cancers.

Gale N, Gnepp DR, Poljak M, et al.
Laryngeal Squamous Intraepithelial Lesions: An Updated Review on Etiology, Classification, Molecular Changes, and Treatment.
Adv Anat Pathol. 2016; 23(2):84-91 [PubMed] Related Publications
Laryngeal carcinogenesis is a multistep process, characterized by an accumulation of genetic changes associated with architectural and cytologic alterations, ranging from squamous hyperplasia to carcinoma in situ and encompassed by the terminology of squamous intraepithelial lesions (SILs). The etiology, classification, genetic changes, and malignant progression of these lesions are reviewed. Tobacco remains the principal etiological factor with gastroesophageal reflux disease recently considered as a possible factor. In contrast, there is little evidence that microbiological agents, especially human papillomavirus infection, are frequently involved in laryngeal carcinogenesis and probably <10% of SILs are driven by biologically active human papillomavirus infection. Light microscopy, despite a degree of subjectivity, remains the mainstay of accurate diagnosis, prognosis, and guidance for a patient's treatment. The currently used classifications, the dysplasia system, squamous intraepithelial neoplasia, and the Ljubljana classification, reflect different standpoints on this important topic. The modified Ljubljana classification, with good interobserver agreement, could be considered as a proposal for a unified classification of laryngeal SILs. This review also briefly discusses recently discovered genetic changes, such as CDKN2A and CTNNB1 genes, and chromosome instability of chromosomes 1 and 7; however, none of these can at present improve histologic diagnosis. Malignant progression of precursor lesions varies from 2% to 74%, according to different studies. Cold-steel microinstruments, CO2 laser, and radiotherapy are used to treat the different grades of precursor lesions. There is as yet no worldwide agreement on the treatment of high-grade lesions and carcinoma in situ.

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