Gene Summary

Gene:CD33; CD33 molecule
Aliases: p67, SIGLEC3, SIGLEC-3
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:myeloid cell surface antigen CD33
Source:NCBIAccessed: 30 August, 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 30 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 30 August, 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: CD33 (cancer-related)

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.

Potter N, Miraki-Moud F, Ermini L, et al.
Single cell analysis of clonal architecture in acute myeloid leukaemia.
Leukemia. 2019; 33(5):1113-1123 [PubMed] Free Access to Full Article Related Publications
We used single cell Q-PCR on a micro-fluidic platform (Fluidigm) to analyse clonal, genetic architecture and phylogeny in acute myeloid leukaemia (AML) using selected mutations. Ten cases of NPM1c mutant AML were screened for 111 mutations that are recurrent in AML and cancer. Clonal architectures were relatively simple with one to six sub-clones and were branching in some, but not all, patients. NPM1 mutations were secondary or sub-clonal to other driver mutations (DNM3TA, TET2, WT1 and IDH2) in all cases. In three of the ten cases, single cell analysis of enriched CD34

Minagawa K, Al-Obaidi M, Di Stasi A
Generation of Suicide Gene-Modified Chimeric Antigen Receptor-Redirected T-Cells for Cancer Immunotherapy.
Methods Mol Biol. 2019; 1895:57-73 [PubMed] Related Publications
Chimeric antigen receptor (CAR)-redirected T-cells are a powerful tool for the treatment of several type of cancers; however, they can cause several adverse effects including cytokine release syndrome, off-target effects resulting in potentially fatal organ damage or even death. Particularly, for CAR T-cells redirected toward acute myeloid leukemia (AML) antigens myelosuppression can be a challenge. The previously validated inducible Caspase9 (iC9) suicide gene system is one of the approaches to control the infused cells in vivo through its activation with a nontherapeutic chemical inducer of dimerizer (CID). We performed a preclinical validation using a model of CD33

Morsink LM, Walter RB, Ossenkoppele GJ
Prognostic and therapeutic role of CLEC12A in acute myeloid leukemia.
Blood Rev. 2019; 34:26-33 [PubMed] Related Publications
CLEC12A has recently been identified as an antigen, expressed on leukemic stem cells and leukemic blasts. Given the fact that this expression profile seems stable throughout diagnosis, treatment and relapse on leukemic blasts and leukemic stem cells, CLEC12A can be considered a highly potent and reliable marker for the detection of measurable residual disease and therefore applicable for risk stratification and prognostication in AML. Low CLEC12A expression on leukemic blasts seems to be independently associated with lower likelihood of achieving complete remission after 1 cycle of induction chemotherapy, shorter event free survival, as well as overall survival, indicating potential prognostic properties of CLEC12A expression itself. Lack of expression on the normal hematopoietic stem and progenitor cells, in contrast to CD123 and CD33, might result in less toxicity regarding cytopenias, making CLEC12A an interesting target for innovating immunotherapies, including monoclonal and bispecific antibodies, antibody-drug conjugates and CAR-T cells therapy.

Herrmann M, Krupka C, Deiser K, et al.
Bifunctional PD-1 × αCD3 × αCD33 fusion protein reverses adaptive immune escape in acute myeloid leukemia.
Blood. 2018; 132(23):2484-2494 [PubMed] Related Publications
The CD33-targeting bispecific T-cell engager (BiTE) AMG 330 proved to be highly efficient in mediating cytolysis of acute myeloid leukemia (AML) cells in vitro and in mouse models. Yet, T-cell activation is correlated with upregulation of programmed cell death-ligand 1 (PD-L1) and other inhibitory checkpoints on AML cells that confer adaptive immune resistance. PD-1 and PD-L1 blocking agents may counteract T-cell dysfunction, however, at the expense of broadly distributed immune-related adverse events (irAEs). We developed a bifunctional checkpoint inhibitory T cell-engaging (CiTE) antibody that combines T-cell redirection to CD33 on AML cells with locally restricted immune checkpoint blockade. This is accomplished by fusing the extracellular domain of PD-1 (PD-1

Georgakopoulos N, Diamantopoulos P, Micci F, et al.
An Adult Patient with Early Pre-B Acute Lymphoblastic Leukemia with t(12;17)(p13;q21)/ZNF384-TAF15.
In Vivo. 2018 Sep-Oct; 32(5):1241-1245 [PubMed] Free Access to Full Article Related Publications
This is a case report of a 46-year-old man diagnosed with early pre-B acute lymphoblastic leukemia (ALL), bearing the translocation t(12;17)(p13;q21) as the sole chromosomal abnormality. This is a rare chromosomal abnormality that has been reported in approximately 25 cases worldwide. FISH analysis revealed a rearrangement of ZNF384 (12p13) and TAF15 (17q12) genes, which is usually associated with a pre-B ALL phenotype with co-expression of the myeloid markers CD13 and/or CD33. ZNF384 encodes a zinc finger protein, which acts as a transcription factor, regulating the expression of several matrix metalloproteinases and TAF15 belongs to the FET (FUS, EWS, and TAF15) family, consisting of RNA and DNA-binding proteins. Unlike most of the cases where CD10 expression was absent or weak, in our case CD10 was highly expressed. The prognostic significance of ZNF384/TAF15 fusion is not very clear since several reports support a generally good prognosis, while others support a poor clinical outcome. Our patient was treated with the German multicenter ALL (GMALL) protocol for B-ALL, but experienced a fulminant gram-negative sepsis and eventually died during induction therapy.

Haubner S, Perna F, Köhnke T, et al.
Coexpression profile of leukemic stem cell markers for combinatorial targeted therapy in AML.
Leukemia. 2019; 33(1):64-74 [PubMed] Free Access to Full Article Related Publications
Targeted immunotherapy in acute myeloid leukemia (AML) is challenged by the lack of AML-specific target antigens and clonal heterogeneity, leading to unwanted on-target off-leukemia toxicity and risk of relapse from minor clones. We hypothesize that combinatorial targeting of AML cells can enhance therapeutic efficacy without increasing toxicity. To identify target antigen combinations specific for AML and leukemic stem cells, we generated a detailed protein expression profile based on flow cytometry of primary AML (n = 356) and normal bone marrow samples (n = 34), and a recently reported integrated normal tissue proteomic data set. We analyzed antigen expression levels of CD33, CD123, CLL1, TIM3, CD244 and CD7 on AML bulk and leukemic stem cells at initial diagnosis (n = 302) and relapse (n = 54). CD33, CD123, CLL1, TIM3 and CD244 were ubiquitously expressed on AML bulk cells at initial diagnosis and relapse, irrespective of genetic characteristics. For each analyzed target, we found additional expression in different populations of normal hematopoiesis. Analyzing the coexpression of our six targets in all dual combinations (n = 15), we found CD33/TIM3 and CLL1/TIM3 to be highly positive in AML compared with normal hematopoiesis and non-hematopoietic tissues. Our findings indicate that combinatorial targeting of CD33/TIM3 or CLL1/TIM3 may enhance therapeutic efficacy without aggravating toxicity in immunotherapy of AML.

Chen H, Chen Y, Liu H, et al.
Integrated Expression Profiles Analysis Reveals Correlations Between the IL-33/ST2 Axis and CD8
Front Immunol. 2018; 9:1179 [PubMed] Free Access to Full Article Related Publications
Soft tissue sarcoma (STS) is a rare solid malignant cancer, and there are few effective treatment options for advanced disease. Cancer immunotherapy is a promising new strategy for STS treatment. IL-33 is a candidate cytokine for immunotherapy that can activate T lymphocytes and modulate antitumor immunity in some cancers. However, the expression and biological role of IL-33 in STS are poorly understood. In this study, we found that the expression of IL-33 and its receptor ST2 was decreased in STS using real-time PCR assays. By analyzing sarcoma data from The Cancer Genome Atlas, we found that higher transcriptional levels of IL-33 and ST2 were associated with a favorable outcome. There were positive correlations between the expression levels of ST2 and CD3E, CD4, CD8A, CD45RO, FOXP3, CD11B, CD33, and IFN-γ. Strong positive correlations between the expression of IFN-γ and CD3E and CD8A were also observed. Moreover, the expression levels of both IL-33 and ST2 were positively correlated with those of CD3E, CD8A, and chemokines that recruit CD8

Kim MY, Yu KR, Kenderian SS, et al.
Genetic Inactivation of CD33 in Hematopoietic Stem Cells to Enable CAR T Cell Immunotherapy for Acute Myeloid Leukemia.
Cell. 2018; 173(6):1439-1453.e19 [PubMed] Free Access to Full Article Related Publications
The absence of cancer-restricted surface markers is a major impediment to antigen-specific immunotherapy using chimeric antigen receptor (CAR) T cells. For example, targeting the canonical myeloid marker CD33 in acute myeloid leukemia (AML) results in toxicity from destruction of normal myeloid cells. We hypothesized that a leukemia-specific antigen could be created by deleting CD33 from normal hematopoietic stem and progenitor cells (HSPCs), thereby generating a hematopoietic system resistant to CD33-targeted therapy and enabling specific targeting of AML with CAR T cells. We generated CD33-deficient human HSPCs and demonstrated normal engraftment and differentiation in immunodeficient mice. Autologous CD33 KO HSPC transplantation in rhesus macaques demonstrated long-term multilineage engraftment of gene-edited cells with normal myeloid function. CD33-deficient cells were impervious to CD33-targeting CAR T cells, allowing for efficient elimination of leukemia without myelotoxicity. These studies illuminate a novel approach to antigen-specific immunotherapy by genetically engineering the host to avoid on-target, off-tumor toxicity.

Kriegsmann K, Löffler H, Eckstein V, et al.
CD7 is expressed on a subset of normal CD34-positive myeloid precursors.
Eur J Haematol. 2018; 101(3):318-325 [PubMed] Related Publications
OBJECTIVE: To improve monitoring of myeloid neoplasms by flow cytometry-based minimal residual disease (MRD) analysis, we analyzed the significance of leukemia-associated immunophenotype (LAIP) markers in 44 patients.
METHODS: In a pilot study cohort, peripheral blood or bone marrow samples from 13 patients with myeloid neoplasms and one case of B lymphoblastic leukemia in complete hematologic remission after allogeneic bone marrow or stem cell transplantation were subjected to selection for leukemia-specific phenotypes by fluorescence-activated cell sorting using individual marker combinations, followed by PCR-based chimerism analysis.
RESULTS: The feasibility of this method could be demonstrated, with selection being successful in 12 cases, including two cases where mixed chimerism was found exclusively in sorted cells. Interestingly, four specimens displayed full donor chimerism in cells expressing the presumably aberrant combination CD34
CONCLUSION: We conclude that the combination CD34

Blatt K, Menzl I, Eisenwort G, et al.
Phenotyping and Target Expression Profiling of CD34
Neoplasia. 2018; 20(6):632-642 [PubMed] Free Access to Full Article Related Publications
Leukemic stem cells (LSCs) are an emerging target of curative anti-leukemia therapy. In acute lymphoblastic leukemia (ALL), LSCs frequently express CD34 and often lack CD38. However, little is known about markers and targets expressed in ALL LSCs. We have examined marker- and target expression profiles in CD34

Yang R, Cai TT, Wu XJ, et al.
Tumour YAP1 and PTEN expression correlates with tumour-associated myeloid suppressor cell expansion and reduced survival in colorectal cancer.
Immunology. 2018; 155(2):263-272 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
The expansion of myeloid-derived suppressor cells (MDSCs) correlates with tumorigenesis in colorectal cancer (CRC). Here, we found a significant association between CD33

Li F, Zhao Y, Wei L, et al.
Tumor-infiltrating Treg, MDSC, and IDO expression associated with outcomes of neoadjuvant chemotherapy of breast cancer.
Cancer Biol Ther. 2018; 19(8):695-705 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: Regulatory T cells(Tregs) and myeloid-derived suppressor cells(MDSCs) represent two immunosuppressive cell populations that are important in the establishment and maintenance of cancer immune tolerance. MDSCs can express IDO and promote immune tolerance via expansion of Treg cell.
METHOD: We use needle biopsy breast cancer tissues prior to neoadjuvant chemotherapy(NCT) staining for CD33, Foxp3 and IDO by immunohistochemistry to evaluate whether they were correlated with subsequent treatment responses in breast cancer.
RESULTS: Expressions of IDO, CD33
CONCLUSION: Tumor-infiltrating MDSCs, Tregs, IDO expression and IDO expression in MDSCs were correlated with clinicopathological features, NCT response, and prognosis of breast cancer patients, suggesting that they might be potential markers for clinical outcomes of NCT and help clinical decision-making for improved therapies for breast cancer.

Petrov JC, Wada M, Pinz KG, et al.
Compound CAR T-cells as a double-pronged approach for treating acute myeloid leukemia.
Leukemia. 2018; 32(6):1317-1326 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Acute myeloid leukemia (AML) bears heterogeneous cells that can consequently offset killing by single-CAR-based therapy, which results in disease relapse. Leukemic stem cells (LSCs) associated with CD123 expression comprise a rare population that also plays an important role in disease progression and relapse. Here, we report on the robust anti-tumor activity of a compound CAR (cCAR) T-cell possessing discrete scFv domains targeting two different AML antigens, CD123, and CD33, simultaneously. We determined that the resulting cCAR T-cells possessed consistent, potent, and directed cytotoxicity against each target antigen population. Using four leukemia mouse models, we found superior in vivo survival after cCAR treatment. We also designed an alemtuzumab safety-switch that allowed for rapid cCAR therapy termination in vivo. These findings indicate that targeting both CD123 and CD33 on AML cells may be an effective strategy for eliminating both AML bulk disease and LSCs, and potentially prevent relapse due to antigen escape or LSC persistence.

Bae J, Hideshima T, Tai YT, et al.
Histone deacetylase (HDAC) inhibitor ACY241 enhances anti-tumor activities of antigen-specific central memory cytotoxic T lymphocytes against multiple myeloma and solid tumors.
Leukemia. 2018; 32(9):1932-1947 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Histone deacetylases (HDAC) are therapeutic targets in multiple cancers. ACY241, an HDAC6 selective inhibitor, has shown anti-multiple myeloma (MM) activity in combination with immunomodulatory drugs and proteasome inhibitors. Here we show ACY241 significantly reduces the frequency of CD138

Li S, Tao Z, Xu Y, et al.
CD33-Specific Chimeric Antigen Receptor T Cells with Different Co-Stimulators Showed Potent Anti-Leukemia Efficacy and Different Phenotype.
Hum Gene Ther. 2018; 29(5):626-639 [PubMed] Related Publications
Acute myeloid leukemia (AML) is a kind of a malignant hematologic tumor caused by uncontrolled repopulation of myeloid hematopoietic stem cells (HSCs). Current therapeutic effects for AML patients are unsatisfactory. In particular, relapsed and refractory AML still have a poor prognosis. T cells modified by chimeric antigen receptor (CAR) was an immunotherapeutic strategy for malignancies, which has a broad developing prospect. Most AML cells overexpress the myeloid antigen CD33. Therefore, CD33-specific CAR-T cells with different co-stimulators (CD28, 4-1BB, or both, referred to as CD33 28z.CAR-T cells, CD33 BBz.CAR-T cells, or CD33 28BBz.CAR-T cells, respectively) were developed to evaluate their efficacy against AML. The effectiveness of three types of CD33 CAR-T cells against AML was verified by specific killing effect to AML cells and prolonged survival of a xenograft mouse model. In terms of CAR-T cell efficacy, especially when transfused into human bodies, the persistence of T cells is also an important index, as it is closely associated with the long-term effect of CAR-T cells. Therefore, the characteristics of three types of CD33 CAR-T cells related to the persistence of T cells were examined. It was found that during expansion, CD33 BBz.CAR-T cells had an increased central memory compartment, while CD33 28z.CAR-T cells were predominantly effector memory T cells. In addition, CD33 28z.CAR-T cells were more inclined to become exhausted. The study suggests that incorporation of 4-1BB in CARs may endow T cells with long-lasting survival ability, thus improving the long-term anti-leukemia effect of CAR-T cells, especially when transfused to the human body.

Corrente F, Bellesi S, Metafuni E, et al.
Role of flow-cytometric immunophenotyping in prediction of BCR/ABL1 gene rearrangement in adult B-cell acute lymphoblastic leukemia.
Cytometry B Clin Cytom. 2018; 94(3):468-476 [PubMed] Related Publications
We performed a retrospective analysis of 88 adult patients with B-ALL diagnosed in our center by a flow-cytometric assessment. Immunophenotypic expression of leukemic cells was explored by simultaneous evaluation of positivity, percentage of expressing cells and median fluorescence intensity (MFI). BCR/ABL1 fusion transcripts were assessed by RT-PCR analysis and were identified in 36 patients (40.9%). CD10 and CD34 were positive in the totality of BCR/ABL1-positive cases. Patients with gene rearrangement had a greater frequency of CD66c, CD13 and CD33 positivity compared with BCR/ABL1-negative cases. Moreover, BCR/ABL1-positive cases exhibited a greater median percentage and MFI values of CD13, CD33, CD66c, CD10, CD34 and CD25 expressions, but a lower median percentage and MFI values of CD38 and CD22 expressions than patients without gene rearrangement. Multivariate logistic regression analysis showed that CD10, CD38 and CD13 expressions were independent predictors for the presence of BCR/ABL1 rearrangement. Predictive probabilities of molecular occurrence based on these markers are proposed. © 2017 International Clinical Cytometry Society.

Kikuchi H, Mimuro H, Kuribayashi F
Resveratrol strongly enhances the retinoic acid-induced superoxide generating activity via up-regulation of gp91-phox gene expression in U937 cells.
Biochem Biophys Res Commun. 2018; 495(1):1195-1200 [PubMed] Related Publications
The membrane bound cytochrome b

Qing X, Panosyan E, Yue C, et al.
Therapy-related myeloid neoplasm in an 18-year-old boy with B-lymphoblastic leukemia.
Exp Mol Pathol. 2017; 103(3):263-266 [PubMed] Related Publications
BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Acute myeloid leukemia or myelodysplastic syndrome during the course of ALL is a rare entity. Some of these cases are therapy-related while the others occur due to lineage switch. The correct diagnosis relies on comparing the immunophenotypes and cytogenetic/molecular alterations of the myeloid neoplasm and the ALL. We present the clinical, pathologic and cytogenetic features of a case of an 18-year-old male with prior treatment for B-lymphoblastic leukemia (B-ALL) who developed therapy-related myeloid neoplasm (t-MN) 4-5years after his initial diagnosis of B-ALL.
CASE PRESENTATION: A 13-year-old boy with no significant past medical history presented to Harbor-UCLA Medical Center (HUMC) in November 2012 with night sweats, fevers and chills, nausea, vomiting, diarrhea, fatigue, weakness, and weight loss. Peripheral blood flow cytometric analysis disclosed B-ALL. The blasts expressed CD10, CD19, CD22 (dim), CD34, CD38, HLA-DR, and TdT, and were negative for CD20, CD13, CD33, CD117, and cytoplasmic MPO. Chromosomal analysis and a supplemental fluorescence in situ hybridization (FISH) study performed on the bone marrow aspirate showed an abnormal karyotype (47,XY,+X,del(9)(p21p21)[4]/46,XY[16]). He achieved remission after induction chemotherapy and remained in remission until March 2016 when bilateral testicular masses were noted. Biopsy of the left testicular mass showed relapsed B-ALL. Cerebrospinal fluid (CSF) contained rare TdT-positive blasts, suggestive of minimal/early involvement by B-ALL. However, there was no evidence of acute leukemia in his bone marrow at this time. He was then treated with COG protocol AALL1331 randomized to blinatumomab arm and achieved second remission. In June 2017, the patient's peripheral blood smear showed 11% circulating monoblasts. By flow cytometry, the blasts expressed CD4, CD11b, CD13, CD15, CD33, CD38, CD56, and CD64. In addition, a few TdT-positive blasts were seen in his CSF cytospin smear. Bone marrow biopsy was subsequently performed which was consistent with evolving acute myeloid leukemia. A diagnosis of myeloid neoplasm, consistent with t-MN was made. Chromosomal analysis and FISH studies performed on his bone marrow aspirate showed normal karyotype (46,XY[20]), negative FISH result for deletion 9p21 locus, and positive KMT2A (MLL) rearrangement, respectively. Despite of chemotherapy, the patient died within one month after diagnosis.
DISCUSSION AND CONCLUSION: Diagnosis of t-MN should be suspected in patients with a history of receiving cytotoxic agents and/or irradiation. In this case study, we diagnosed t-MN with KMT2A rearrangement in a patient with history of B-ALL with 9p deletion and gain of X chromosome. Unusual features associated with this case are discussed.

Menguy S, Prochazkova-Carlotti M, Beylot-Barry M, et al.
PD-L1 and PD-L2 Are Differentially Expressed by Macrophages or Tumor Cells in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type.
Am J Surg Pathol. 2018; 42(3):326-334 [PubMed] Related Publications
As checkpoint molecules' inhibition may represent a therapeutic option in relapsing cases, we assessed programmed death ligands' (PD-L1/PD-L2) expression in a series of 29 primary cutaneous diffuse large B-cell lymphoma, leg-type (PCDLBCL-LT) cases. Double immunostaining for either PD-L1 or PD-L2 was associated either with PAX5 staining to evaluate tumor cells or with CD68 or CD163 staining for macrophages. The microenvironment of PCDLBCL-LT was characterized by immunostainings for CD3 (tumor-infiltrating lymphocytes), FOXP3 (regulatory T cells), programmed cell death-1, and CD33 (myeloid-derived suppressor cells). The 9p24.1 locus encoding for PD-L1/PD-L2 was evaluated by fluorescence in situ hybridization. A PD-L1 expression was observed in all cases. However, double staining with PD-L1/PAX5 identified only 1 case harboring PD-L1 expression by tumor cells. All cases displayed PD-L1 expression by numerous immune cells, characterized as CD68 CD163 M2 macrophages. A normal fluorescence in situ hybridization pattern was observed in 21 of 26 cases. Three cases (11.5%) harbored a low polysomy status including the case with PD-L1 expression by tumor cells. Interestingly, 2 cases (7.7%) exhibited a PD-L1/PD-L2 locus break-apart pattern, and PD-L2 expression by tumor cells was observed. PD-L2 expression by tumor cells was not observed in the 24 cases without 9p24.1 rearrangement. Treating patients with relapsing PCDLBCL-LT by using immune checkpoint inhibitors may have an indirect effect through immune cells, except in rare cases with 9p24.1 rearrangement leading to PD-L2 expression by tumor cells. Reprogramming tumor-associated macrophages with anticancer therapies is appealing in such lymphoma subtypes wherein M2 macrophages represent the majority of immune cells.

Zhou J, Liu M, Sun H, et al.
Hepatoma-intrinsic CCRK inhibition diminishes myeloid-derived suppressor cell immunosuppression and enhances immune-checkpoint blockade efficacy.
Gut. 2018; 67(5):931-944 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
OBJECTIVE: Myeloid-derived suppressor cells (MDSCs) contribute to tumour immunosuppressive microenvironment and immune-checkpoint blockade resistance. Emerging evidence highlights the pivotal functions of cyclin-dependent kinases (CDKs) in tumour immunity. Here we elucidated the role of tumour-intrinsic CDK20, or cell cycle-related kinase (CCRK) on immunosuppression in hepatocellular carcinoma (HCC).
DESIGN: Immunosuppression of MDSCs derived from patients with HCC and relationship with CCRK were determined by flow cytometry, expression analyses and co-culture systems. Mechanistic studies were also conducted in liver-specific
RESULTS: Tumour-infiltrating CD11b
CONCLUSION: Our results delineate an immunosuppressive mechanism of the hepatoma-intrinsic CCRK signalling and highlight an overexpressed kinase target whose inhibition might empower HCC immunotherapy.

Kelm RJ, Lamba GS, Levis JE, Holmes CE
Characterization of purine-rich element binding protein B as a novel biomarker in acute myelogenous leukemia prognostication.
J Cell Biochem. 2018; 119(2):2073-2083 [PubMed] Related Publications
Acute myelogenous leukemia (AML) is an aggressive hematologic cancer characterized by infiltration of proliferative, clonal, abnormally differentiated cells of myeloid lineage in the bone marrow and blood. Malignant cells in AML often exhibit chromosomal and other genetic or epigenetic abnormalities that are useful in prognostic risk assessment. In this study, the relative expression and novel single-stranded DNA (ssDNA) binding function of purine-rich element binding proteins A and B (Purα and Purβ) were systematically evaluated in established leukemia cell lines and in lineage committed myeloid cells isolated from patients diagnosed with a hematologic malignancy. Western blotting revealed that Purα and Purβ are markedly elevated in CD33

Cai TT, Ye SB, Liu YN, et al.
LMP1-mediated glycolysis induces myeloid-derived suppressor cell expansion in nasopharyngeal carcinoma.
PLoS Pathog. 2017; 13(7):e1006503 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Myeloid-derived suppressor cells (MDSCs) are expanded in tumor microenvironments, including that of Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC). The link between MDSC expansion and EBV infection in NPC is unclear. Here, we show that EBV latent membrane protein 1 (LMP1) promotes MDSC expansion in the tumor microenvironment by promoting extra-mitochondrial glycolysis in malignant cells, which is a scenario for immune escape initially suggested by the frequent, concomitant detection of abundant LMP1, glucose transporter 1 (GLUT1) and CD33+ MDSCs in tumor sections. The full process has been reconstituted in vitro. LMP1 promotes the expression of multiple glycolytic genes, including GLUT1. This metabolic reprogramming results in increased expression of the Nod-like receptor family protein 3 (NLRP3) inflammasome, COX-2 and P-p65 and, consequently, increased production of IL-1β, IL-6 and GM-CSF. Finally, these changes in the environment of malignant cells result in enhanced NPC-derived MDSC induction. One key step is the physical interaction of LMP1 with GLUT1 to stabilize the GLUT1 protein by blocking its K48-ubiquitination and p62-dependent autolysosomal degradation. This work indicates that LMP1-mediated glycolysis regulates IL-1β, IL-6 and GM-CSF production through the NLRP3 inflammasome, COX-2 and P-p65 signaling pathways to enhance tumor-associated MDSC expansion, which leads to tumor immunosuppression in NPC.

Laing AA, Harrison CJ, Gibson BES, Keeshan K
Unlocking the potential of anti-CD33 therapy in adult and childhood acute myeloid leukemia.
Exp Hematol. 2017; 54:40-50 [PubMed] Related Publications
Acute myeloid leukemia (AML) develops when there is a block in differentiation and uncontrolled proliferation of myeloid precursors, resulting in bone marrow failure. AML is a clinically, morphologically, and genetically heterogeneous disease, and biological differences between adult and childhood AML have been identified. AML comprises 15%-20% of all children <15 years of age diagnosed with acute leukemia. Relapse occurs in up to 40% of children with AML and is the most common cause of death. Relapse arises from leukemic stem cells (LSCs) that persist after conventional chemotherapy. The treatment of AML is challenging, and new strategies to target LSCs are required. The cell surface marker CD33 has been identified as a therapeutic target, and novel anti-CD33 immunotherapies are promising new agents in the treatment of AML. This review summarizes recent developments emphasizing the genetic differences in adult and childhood AML and highlights the rationale for CD33 as a target for therapy in all age groups.

Lamba JK, Chauhan L, Shin M, et al.
CD33 Splicing Polymorphism Determines Gemtuzumab Ozogamicin Response in De Novo Acute Myeloid Leukemia: Report From Randomized Phase III Children's Oncology Group Trial AAML0531.
J Clin Oncol. 2017; 35(23):2674-2682 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Purpose Gemtuzumab ozogamicin (GO), a CD33-targeted immunoconjugate, is a re-emerging therapy for acute myeloid leukemia (AML). CD33 single nucleotide polymorphism rs12459419 C>T in the splice enhancer region regulates the expression of an alternatively spliced CD33 isoform lacking exon2 (D2-CD33), thus eliminating the CD33 IgV domain, which is the antibody-binding site for GO, as well as diagnostic immunophenotypic panels. We aimed to determine the impact of the genotype of this splicing polymorphism in patients with AML treated with GO-containing chemotherapy. Patients and Methods CD33 splicing single nucleotide polymorphism was evaluated in newly diagnosed patients with AML randomly assigned to receive standard five-course chemotherapy alone (No-GO arm, n = 408) or chemotherapy with the addition of two doses of GO once during induction and once during intensification (GO arm, n = 408) as per the Children's Oncology Group AAML0531 trial. Results The rs12459419 genotype was CC in 415 patients (51%), CT in 316 patients (39%), and TT in 85 patients (10%), with a minor allele frequency of 30%. The T allele was significantly associated with higher levels of D2-CD33 transcript ( P < 1.0E

Heczey A, Louis CU, Savoldo B, et al.
CAR T Cells Administered in Combination with Lymphodepletion and PD-1 Inhibition to Patients with Neuroblastoma.
Mol Ther. 2017; 25(9):2214-2224 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Targeting disialoganglioside (GD2) on neuroblastoma (NB) with T cells expressing a first-generation chimeric antigen receptor (CAR) was safe, but the cells had poor expansion and long-term persistence. We developed a third-generation GD2-CAR (GD2-CAR3) and hypothesized that GD2-CAR3 T cells (CARTs) would be safe and effective. This phase 1 study enrolled relapsed or refractory NB patients in three cohorts. Cohort 1 received CART alone, cohort 2 received CARTs plus cyclophosphamide and fludarabine (Cy/Flu), and cohort 3 was treated with CARTs, Cy/Flu, and a programmed death-1 (PD-1) inhibitor. Eleven patients were treated with CARTs. The infusions were safe, and no dose-limiting toxicities occurred. CARTs were detectable in cohort 1, but the lymphodepletion induced by Cy/Flu increased circulating levels of the homeostatic cytokine interleukin (IL)-15 (p = 0.003) and increased CART expansion by up to 3 logs (p = 0.03). PD-1 inhibition did not further enhance expansion or persistence. Antitumor responses at 6 weeks were modest. We observed a striking expansion of CD45/CD33/CD11b/CD163

Lerman I, Garcia-Hernandez ML, Rangel-Moreno J, et al.
Infiltrating Myeloid Cells Exert Protumorigenic Actions via Neutrophil Elastase.
Mol Cancer Res. 2017; 15(9):1138-1152 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Tissue infiltration and elevated peripheral circulation of granulocytic myeloid-derived cells is associated with poor outcomes in prostate cancer and other malignancies. Although myeloid-derived cells have the ability to suppress T-cell function, little is known about the direct impact of these innate cells on prostate tumor growth. Here, it is reported that granulocytic myeloid-derived suppressor cells (MDSC) are the predominant tumor-infiltrating cells in prostate cancer xenografts established in athymic nude mice. MDSCs significantly increased in number in the peripheral circulation as a function of xenograft growth and were successfully depleted

Mancini I, Righi A, Gambarotti M, et al.
Phenotypic and molecular differences between giant-cell tumour of soft tissue and its bone counterpart.
Histopathology. 2017; 71(3):453-460 [PubMed] Related Publications
AIMS: Giant-cell tumour (GCT) of soft tissue (GCT-ST) is a primary soft tissue neoplasm that is histologically similar to GCT of bone (GCT-B). Recently, it has been reported that >90% of GCT-Bs have a driver mutation in the H3F3A gene. As the relationship between GCT-ST and GCT-B is unclear, the aim of this study was to compare a series of GCT-STs and GCT-Bs with regard to the presence of H3F3A mutations and several immunophenotypic markers.
METHODS AND RESULTS: Eight GCT-STs were retrieved from our institutional archives. Fifteen GCT-Bs served as controls. Direct sequencing for H3F3A mutations in coding regions between codons 1 and 42, including the hotspot codons (28, 35, and 37), was performed on DNA extracted from formalin-fixed paraffin-embedded tissue. Tumours were studied immunohistochemically for the expression of CD14, CD33, RANKL, RANK, p63, and the osteoblastic markers SATB2 and RUNX2. None of the seven GCT-STs that could be analysed showed H3F3A mutations, whereas 14 GCT-Bs (93.3%) were mutated. All eight GCT-STs were positive for RANK and RUNX2, whereas RANKL and SATB2 were detected in only two cases (25%). CD14 was detected only in mononuclear elements, whereas multinucleated giant cells and a proportion of the mononuclear population expressed CD33. Few mononuclear cells of GCT-STs expressed p63. In comparison, GCT-Bs showed higher expression of p63 (14 of 15 cases with >50% of positive mononuclear cells), RANKL, and SATB2, whereas CD14, CD33, RANK and RUNX2 were similarly expressed.
CONCLUSIONS: Although GCT-ST and GCT-B are similar in histological appearance, our results indicate that they are immunophenotypically and genetically distinct.

Jiang Y, Xu P, Yao D, et al.
CD33, CD96 and Death Associated Protein Kinase (DAPK) Expression Are Associated with the Survival Rate and/or Response to the Chemotherapy in the Patients with Acute Myeloid Leukemia (AML).
Med Sci Monit. 2017; 23:1725-1732 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND Leukemia stem cells (LSC) are involved in the incidence, drug resistance, and relapse of leukemia while LSC-related antigen CD33, CD96, and DAPK expression in AML and its prognosis is still unclear. This study explored LSC-related antigens expression in acute myeloid leukemia (AML) and its prognosis. MATERIAL AND METHODS A total of 156 cases of AML patients were enrolled in the experiment. The expression of CD33, CD96, and DAPK in CD34+CD38-CD123+ LSC were tested by flow cytometry. The survival curve was established using the Kaplan-Meier method. RESULTS Among different subtypes of AML, the positive rate of CD33 was M3> M5> M1> M2> M4; for CD96 it was M5> M4> M2> M3> M1; and for DAPK it was M3> M2> M5> M4> M1. After chemotherapy, the response rate in CD33 and CD96 high expression groups, and DAPK low expression group was significantly lower than the groups with CD33 low expression, CD96 low expression, and DAPK high expression. The median survival time in the CD33 high expression group was markedly lower than the CD33 low expression group (36.5 months). The CD96 high expression group exhibited obviously shorter median survival time than the CD96 low expression group. The DAPK high expression group exhibited longer median survival time than the DAPK low expression group. CONCLUSIONS CD33 and CD96 overexpression, and DAPK downregulation in the LSC of AML patients were associated with poor chemotherapy effect and prognosis, and higher recurrence rate.

Yaguchi A, Ishibashi T, Terada K, et al.
EP300-ZNF384 fusion gene product up-regulates GATA3 gene expression and induces hematopoietic stem cell gene expression signature in B-cell precursor acute lymphoblastic leukemia cells.
Int J Hematol. 2017; 106(2):269-281 [PubMed] Related Publications
ZNF384-related fusion genes are associated with a distinct subgroup of B-cell precursor acute lymphoblastic leukemias in childhood, with a frequency of approximately 3-4%. We previously identified a novel EP300-ZNF384 fusion gene. Patients with the ZNF384-related fusion gene exhibit a hematopoietic stem cell (HSC) gene expression signature and characteristic immunophenotype with negative or low expression of CD10 and aberrant expression of myeloid antigens, such as CD33 and CD13. However, the molecular basis of this pathogenesis remains completely unknown. In the present study, we examined the biological effects of EP300-ZNF384 expression induced by retrovirus-mediated gene transduction in an REH B-cell precursor acute lymphoblastic leukemia cell line, and observed the acquisition of the HSC gene expression signature and an up-regulation of GATA3 gene expression, as assessed by microarray analysis. In contrast, the gene expression profile induced by wild-type ZNF384 in REH cells was significantly different from that by EP300-ZNF384 expression. Together with the results of reporter assays, which revealed the enhancement of GATA3-promoter activity by EP300-ZNF384 expression, these findings suggest that EP300-ZNF384 mediates GATA3 gene expression and may be involved in the acquisition of the HSC gene expression signature and characteristic immunophenotype in B-cell precursor acute lymphoblastic leukemia cells.

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