Gene Summary

Gene:SH2D1A; SH2 domain containing 1A
Summary:This gene encodes a protein that plays a major role in the bidirectional stimulation of T and B cells. This protein contains an SH2 domain and a short tail. It associates with the signaling lymphocyte-activation molecule, thereby acting as an inhibitor of this transmembrane protein by blocking the recruitment of the SH2-domain-containing signal-transduction molecule SHP-2 to its docking site. This protein can also bind to other related surface molecules that are expressed on activated T, B and NK cells, thereby modifying signal transduction pathways in these cells. Mutations in this gene cause lymphoproliferative syndrome X-linked type 1 or Duncan disease, a rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus, with symptoms including severe mononucleosis and malignant lymphoma. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:SH2 domain-containing protein 1A
Source:NCBIAccessed: 13 March, 2017


What does this gene/protein do?
Show (6)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 13 March 2017 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.

  • Herpesvirus 4, Human
  • B-Lymphocytes
  • Genetic Predisposition
  • Natural Killer Cells
  • Adolescents
  • Childhood Cancer
  • Signaling Lymphocytic Activation Molecule Family
  • X Chromosome
  • Fatal Outcome
  • Signal Transduction
  • Lymphoproliferative Disorders
  • T-Lymphocytes
  • Carrier Proteins
  • Exons
  • Intracellular Signaling Peptides and Proteins
  • NK Cell Lectin-Like Receptor Subfamily K
  • Signaling Lymphocytic Activation Molecule Associated Protein
  • Young Adult
  • Base Sequence
  • SH2D1A protein, human
  • Molecular Sequence Data
  • Hodgkin Lymphoma
  • src Homology Domains
  • CD Antigens
  • Signaling Lymphocytic Activation Molecule Family Member 1
  • Cell Surface Receptors
  • Pedigree
  • Vasculitis, Central Nervous System
  • Infectious Mononucleosis
  • B-Cell Lymphoma
  • Non-Hodgkin Lymphoma
  • Siblings
  • DNA Mutational Analysis
  • Perforin
  • DNA Primers
  • Mutation
  • Infant
  • Missense Mutation
  • Antineoplastic Agents
  • Epstein-Barr Virus Infections
Tag cloud generated 13 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

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: SH2D1A (cancer-related)

Palamuthusingam D, Mantha M, Oliver K, et al.
Mini review: A unique case of crescentic C3 glomerulonephritis.
Nephrology (Carlton). 2017; 22(3):261-264 [PubMed] Related Publications
Kidney involvement is an under-recognized complication of non-Hodgkin lymphomas. They occur in a variety of mechanisms and differ widely in their clinical presentation. We take this opportunity to report a case of a 65 year-old man who developed a rapidly progressive glomerulonephritis within days after completing his first cycle of R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisolone) chemotherapy for newly diagnosed mantle cell lymphoma. He was odematous, hypertensive, oliguric with nephrotic range proteinuria and an active urine sediment. A renal biopsy showed a crescentic C3 glomerulonephritis (C3GN) with no evidence endocapillary or mesangial hypercellularity. He was promptly treated with immunosuppression and dialysis, with resumption of his chemotherapy. Genetic testing on complement proteins revealed a homozygous deletion spanning the CFHR1 and CFHR3 genes. Crescentic C3GN is a rare form of kidney injury, and this is the first known case of lymphoma-associated kidney involvement manifesting as C3GN. This article explores the possible mechanism of disease and reviews the literature of lymphoma-related kidney disease.

Nakatsuka SI, Yutani C, Kurashige M, et al.
An unusual case of Epstein-Barr virus-positive large B-cell lymphoma lacking various B-cell markers.
Diagn Pathol. 2017; 12(1):15 [PubMed] Free Access to Full Article Related Publications
BACKGROUD: Epstein-Barr virus (EBV) is associated with B-cell lymphoma in various conditions, such as immunodeficiency and chronic inflammation. We report an unusual case of EBV-positive diffuse large B-cell lymphoma (DLBCL) lacking the expression of many B-cell markers.
CASE PRESENTATION: An 83-year-old man presented with a submandibular tumor. Histology of a lymph node biopsy specimen revealed diffuse proliferation of centroblast- or immunoblast-like lymphoid cells with plasmacytic differentiation. Scattered Hodgkin/Reed-Sternberg-like cells were also visible. A routine immunohistochemistry antibody panel revealed that the tumor cells were negative for B-cell and T-cell markers (i.e., CD3, CD19, CD20, CD38, CD45RO, CD79a, CD138, and Pax-5), but were positive for CD30 and MUM-1, not defining the lineage of tumor cells. The final diagnosis of EBV-positive DLBCL was confirmed based on the expression of B-cell-specific transcription factors (Oct-2 and BOB.1), PCR-based identification of monoclonal rearrangement of the immunoglobulin genes, and the presence of EBV-encoded small RNAs in the tumor cells (identified using in situ hybridization).
CONCLUSION: The downregulation of broad band of B-cell markers in the present case with EBV-positive DLBCL posed a diagnostic dilemma, as the possible diagnoses included differentiation from anaplastic large cell lymphoma and CD20-negative B-cell lymphomas. Results of immunohistochemical panel including B-cell-specific transcription factors and gene rearrangement analyses critically support the correct diagnosis.

Barabas AZ, Cole CD, Graeff RM, et al.
Suppression of tumor growth by a heterologous antibody directed against multiple myeloma dominant CD38 antigen in SCID mice injected with multiple myeloma cells.
Hum Antibodies. 2016; 24(3-4):53-57 [PubMed] Related Publications
Employing passive immunization - using a heterologous anti-CD38 IgG antibody containing serum - in SCID mice injected subcutaneously with human multiple myeloma cells, we have shown that treatments with the antiserum - especially in the presence of complement - significantly decreased cancer growth. However, administered antibody and complement was not sufficient in amount to prevent cancer cell multiplication and cancer growth expansion to a satisfactory degree. Larger volumes of the same components more than likely would have further reduced cancer growth and prolonged the life of mice. In control mice, cancer growth progressed faster proving that lytic immune response against multiple myeloma cells is necessary for cancer cell kill.

Barabas AZ, Cole CD, Graeff RM, et al.
A novel modified vaccination technique produces IgG antibodies that cause complement-mediated lysis of multiple myeloma cells carrying CD38 antigen.
Hum Antibodies. 2016; 24(3-4):45-51 [PubMed] Related Publications
Objectives were to: 1) induce a lytic IgG antibody (ab) response (via the so called `third vaccination method') against CD38 antigen (ag) residing on the extra-cellular domain of multiple myeloma (MM) cells in recipient rabbits, by combining the CD38 ag with donor-derived anti-CD38 ag lytic IgG ab into an immune complex (IC); and 2) determine whether abs produced would cause complement-mediated lysis (in vitro) of human MM cells containing CD38 ag. The vaccine was created in a two-step process. First, ab (rabbit anti-CD38 ag IgG ab) was raised in donor rabbits by injections of low molecular weight soluble CD38 ag in Freund's complete adjuvant (FCA) and aqueous solution. Second, transfer of pathogenic lytic IgG ab response into recipient rabbits was achieved by injections of ICs composed of CD38 ag and homologous anti-CD38 ag IgG ab. Consequently, recipient rabbits produced the same ab with the same specificity against the target ag as was present in the inoculum, namely agglutinating, precipitating and lytic (as demonstrated in vitro). In an in vitro study, in the presence of complement, donor and recipient rabbits' immune sera caused lysis of CD38 ag associated human MM cells. The most effective lytic ab response causing sera were those from donor rabbits injected with CD38 ag in FCA and those from rabbits injected with ICs, especially when they were administered in adjuvants. These results provided proof of concept that the third vaccination method has good potential as a stand-alone and efficacious method of controlling cancer.

Campregher PV, Petroni RC, Muto NH, et al.
A Novel Assay for the Identification of NOTCH1 PEST Domain Mutations in Chronic Lymphocytic Leukemia.
Biomed Res Int. 2016; 2016:4247908 [PubMed] Free Access to Full Article Related Publications
Aims. To develop a fast and robust DNA-based assay to detect insertions and deletions mutations in exon 34 that encodes the PEST domain of NOTCH1 in order to evaluate patients with chronic lymphocytic leukemia (CLL). Methods. We designed a multiplexed allele-specific polymerase chain reaction (PCR) combined with a fragment analysis assay to detect specifically the mutation c.7544_7545delCT and possibly other insertions and deletions in exon 34 of NOTCH1. Results. We evaluated our assay in peripheral blood samples from two cohorts of patients with CLL. The frequency of NOTCH1 mutations was 8.4% in the first cohort of 71 unselected CLL patients. We then evaluated a second cohort of 26 CLL patients with known cytogenetic abnormalities that were enriched for patients with trisomy 12. NOTCH1 mutations were detected in 43.7% of the patients with trisomy 12. Conclusions. We have developed a fast and robust assay combining allele-specific PCR and fragment analysis able to detect NOTCH1 PEST domain insertions and deletions.

Zamani-Ahmadmahmudi M, Aghasharif S, Ilbeigi K
Prognostic efficacy of the human B-cell lymphoma prognostic genes in predicting disease-free survival (DFS) in the canine counterpart.
BMC Vet Res. 2017; 13(1):17 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Canine B-cell lymphoma is deemed an ideal model of human non-Hodgkin's lymphoma where the lymphomas of both species share similar clinical features and biological behaviors. However there are some differences between tumor features in both species. In the current study, we sought to evaluate the prognostic efficacy of human B-cell lymphoma prognostic gene signatures in canine B-cell lymphoma.
METHODS: The corresponding probe sets of 36 human B-cell lymphoma prognostic genes were retrieved from 2 canine B-cell lymphoma microarray datasets (GSE43664 and GSE39365) (76 samples), and prognostic probe sets were thereafter detected using the univariate and multivariate Cox proportional-hazard model and the Kaplan-Meier analysis. The two datasets were employed both as training sets and as external validation sets for each other. Results were confirmed using quantitative real-time PCR (qRT-PCR) analysis.
RESULTS: In the univariate analysis, CCND1, CCND2, PAX5, CR2, LMO2, HLA-DQA1, P53, CD38, MYC-N, MYBL1, and BIRCS5 were associated with longer disease-free survival (DFS), while CD44, PLAU, and FN1 were allied to shorter DFS. However, the multivariate Cox proportional-hazard analysis confirmed CCND1 and BIRCS5 as prognostic genes for canine B-cell lymphoma. qRT-PCR used for verification of results indicated that expression level of CCND1 was significantly higher in B-cell lymphoma patients with the long DFS than ones with the short DFS, while expression level of BIRCS5 wasn't significantly different between two groups.
CONCLUSION: Our results confirmed CCND1 as important gene that can be used as a potential predictor in this tumor type.

Shabestari RM, Safa M, Alikarami F, et al.
CREB knockdown inhibits growth and induces apoptosis in human pre-B acute lymphoblastic leukemia cells through inhibition of prosurvival signals.
Biomed Pharmacother. 2017; 87:274-279 [PubMed] Related Publications
A majority of acute lymphoblastic leukemia patients overexpress CREB in the bone marrow. However, the functional significance of this up-regulation and the detailed molecular mechanism behind the regulatory effect of CREB on the growth of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cells has not been elucidated. We demonstrated here that CREB knockdown induced apoptosis and impaired growth of BCP-ALL NALM-6 cells which was associated with caspase activation. The gene expression levels of prosurvival signals Bcl-2, Mcl-1, Bcl-xL, survivin and XIAP were down-regulated upon CREB suppression. These findings indicate a critical role for CREB in proliferation, survival, and apoptosis of BCP-ALL cells. The data also suggest that CREB could possibly serve as potential therapeutic target in BCP-ALL.

Zhang B, Zhang W, Yan L, Wang D
The association between MTHFR gene C677T polymorphism and ALL risk based on a meta-analysis involving 17,469 subjects.
Clin Chim Acta. 2017; 466:85-92 [PubMed] Related Publications
BACKGROUND: The methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism is closely related to the acute lymphoblastic leukaemia (ALL) indicated by many previous epidemiologic studies. However, their conclusions were still conflicting.
METHODS: Our aim is to evaluate their associations using a more comprehensive updated meta-analysis. Electronic searches were conducted to select published studies prior to February, 2016.
RESULTS: Totally, 39 case-control studies including 6551 ALL cases and 10,918 controls were selected in current meta-analysis. The association was detected significantly between MTHFR C677T polymorphism and ALL reducing susceptibility.
CONCLUSIONS: Our results indicate that the MTHFR C677T polymorphism may be a promising ALL biomarker and studies to explore the protein levels of the variants and their functional role are required for the definitive conclusions.

Oliveira CC, Maciel-Guerra H, Kucko L, et al.
Double-hit lymphomas: clinical, morphological, immunohistochemical and cytogenetic study in a series of Brazilian patients with high-grade non-Hodgkin lymphoma.
Diagn Pathol. 2017; 12(1):3 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Double-hit lymphomas (DHL) are rare high-grade neoplasms characterized by two translocations: one involving the gene MYC and another involving genes BCL2 or BCL6, whose diagnosis depends on cytogenetic examination. This research studied DHL and morphological and/or immunophenotypic factors associated with the detection of these translocations in a group of high-grade non-Hodgkin lymphoma cases.
METHOD: Clinical and morphological reviews of 120 cases diagnosed with diffuse large B-cell lymphoma and Burkitt lymphoma were conducted. Immunohistochemistry (CD20, CD79a, PAX5, CD10, Bcl6, Bcl2, MUM1, TDT and Myc) and fluorescence in situ hybridization for detection of MYC, BCL2 and BCL6 gene translocations were performed in a tissue microarray platform.
RESULTS: Three cases of DHL were detected: two with translocations of MYC and BCL2 and one with translocations of MYC and BCL6, all leading to death in less than six months. Among 90 cytogenetically evaluable biopsies, associations were determined between immunohistochemistry and fluorescence in situ hybridization for MYC (p = 0.036) and BCL2 (p = 0.001). However, these showed only regular agreement, indicated by Kappa values of 0.23 [0.0;0.49] and 0.35 [0.13;0.56], respectively. "Starry sky" morphology was strongly associated with MYC positivity (p = 0.01). The detection of three cases of DHL, all resulting in death, confirms the rarity and aggressiveness of this neoplasm.
CONCLUSIONS: The "starry sky" morphological pattern and immunohistochemical expression of Myc and Bcl2 represent possible selection factors for additional cytogenetic diagnostic testing.

Eskandari-Nasab E, Hashemi M, Hasani SS, et al.
Evaluation of functional RAGE gene polymorphisms in childhood acute lymphoblastic leukemia-A case-control study from Iran.
Nucleosides Nucleotides Nucleic Acids. 2017; 36(3):170-180 [PubMed] Related Publications
We examined the possible relationship between three RAGE polymorphisms, -429C/T, -374 T/A, and 63-bp deletion, and susceptibility to childhood acute lymphoblastic leukemia (ALL) in an Iranian population. This study included 75 ALL patients and 115 healthy subjects. Genotyping was performed using HEXA-ARMS-polymerase chain reaction. We found no significant association among RAGE gene polymorphisms and the risk for ALL at genotype, allelic and haplotype levels (P > 0.05). The hemoglobin levels were higher in patients with RAGE -374 TT than in the TA carriers (P = 0.019). Our results demonstrated that the RAGE gene variations were not associated with risk of pediatrics ALL.

Cho BB, Kelting SM, Gru AA, et al.
Cyclin D1 expression and polysomy in lymphocyte-predominant cells of nodular lymphocyte-predominant Hodgkin lymphoma.
Ann Diagn Pathol. 2017; 26:10-15 [PubMed] Related Publications
Cyclin D1 protein expression in lymphocytes is classically associated with mantle cell lymphoma. Although increasingly recognized in other lymphoproliferative disorders, cyclin D1 expression and CCND1 gene abnormalities have not been well studied in nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). Using a double stain for CD20/cyclin D1, we quantified cyclin D1 expression in 10 cases of NLPHL and correlated those findings with SOX11 expression, CCND1 gene abnormalities, and clinical data. For comparison, we examined 5 cases of T cell-/histiocyte-rich large B-cell lymphoma (THRLBCL). All cases of NLPHL stained for cyclin D1 showed at least rare positivity in lymphocyte-predominant (LP) cells. In 4 cases, at least 20% of LP cells were positive for CD20/cyclin D1. Neither SOX11 expression nor CCND1 gene rearrangement was found in any of the cases, but fluorescence in situ hybridization showed a proportion of the large cells with 3 to 4 copies of nonfused IGH and CCND1 signals or 3 intact CCND1 break-apart signals. Further study with CCND1/CEP11 showed polysomy in 6 of 9 cases with cyclin D1 expression and 5 of 16 NLPHL not examined for cyclin D1. Two of 5 cases of THRLBCL showed rare positive staining for CD20/cyclin D1; 1 case showed polysomy with CCND1/CEP11. Results show that cyclin D1 may be expressed in LP cells without SOX11 expression or CCND1 translocation. Polysomy with increased copies of CCND1 may account for cyclin D1 expression in some cases. Cyclin D1 expression is not useful for distinguishing NLPHL from THRLBCL and has no apparent clinical significance in NLPHL.

Fernández C, Bellosillo B, Ferraro M, et al.
MicroRNAs 142-3p, miR-155 and miR-203 Are Deregulated in Gastric MALT Lymphomas Compared to Chronic Gastritis.
Cancer Genomics Proteomics. 2017; 14(1):75-82 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Over the last years, our knowledge on pathogenesis of gastric MALT lymphoma has greatly improved, but its morphological diagnosis is still hampered by overlapping histological features with advanced chronic gastritis. MicroRNAs are deregulated in lymphomas, but their role and usefulness in gastric MALT lymphoma has not been extensively investigated.
MATERIALS AND METHODS: We analyzed the expression of 384 miRNAs using TaqMan microRNA assay in a training series of 10 gastric MALT lymphomas, 3 chronic gastritis and 2 reactive lymph nodes. Then, significantly deregulated miRNAs were individually assessed by real-time PCR in a validation series of 16 gastric MALT lymphomas and 12 chronic gastritis.
RESULTS: Gastric MALT lymphoma is characterized by a specific miRNA expression profile. Among the differentially expressed miRNAs, a significant overexpression of miR-142-3p and miR-155 and down-regulation of miR-203 was observed in gastric MALT lymphoma when compared to chronic gastritis.
CONCLUSION: miR-142-3p, miR-155 and miR-203 expression levels might be helpful biomarkers for the differential diagnosis between gastric MALT lymphomas and chronic gastritis.

Miao Y, Lin P, Wang W, et al.
CCND1-IGH Fusion-Amplification and MYC Copy Number Gain in a Case of Pleomorphic Variant Mantle Cell Lymphoma.
Am J Clin Pathol. 2016; 146(6):747-752 [PubMed] Related Publications
OBJECTIVES: Mantle cell lymphoma (MCL) may present de novo or undergo progression to a clinically aggressive variant, known as a blastoid or pleomorphic variant. We report an unusual case of classic MCL in a 78-year-old man with a typical immunophenotype, including CD5 positivity, who subsequently relapsed with CD5-negative pleomorphic variant MCL.
METHODS: Biopsy specimens were evaluated using Wright-Giemsa-stained or H&E-stained sections, flow cytometry, immunohistochemistry, conventional cytogenetic, next-generation sequencing, and fluorescence in situ hybridization.
RESULTS: The patient continued to be refractory to intensive chemotherapy and radiation therapy. Initial conventional cytogenetic analysis showed a complex karyotype with amplification of the CCND1-IGH fusion gene on the der(14): 44, Y, t(X;2)(p22.3;q21), del(2)(p21), del(6)(p23), add(7)(p22),-9, del(9)(p22), add(11)(q13),-13, add(14)(p11.2), der(14)t(11;14)(q13;q32)hsr(14)(q32), add(18)(q23), add(21)(p11.1),-22,+mar[12]. A repeat biopsy revealed MCL, pleomorphic variant, with loss of CD5 expression and extra copies of the MYC CONCLUSIONS: CCND1-IGH fusion-amplification with MYC copy number gain is extremely rare and may play a role in disease progression in a subset of MCL cases.

Middleton RJ, Kam WW, Liu GJ, Banati RB
Epigenetic Silencing of the Human 18 kDa Translocator Protein in a T Cell Leukemia Cell Line.
DNA Cell Biol. 2017; 36(2):103-108 [PubMed] Related Publications
The mitochondrial membrane 18 kDa translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is constitutively expressed in most organs, most abundantly in hormonal tissue and cells of mononuclear phagocyte lineage, while in the brain, TSPO expression is induced in the wake of injury, inflammation, and neurodegeneration. Increased TSPO expression is also prominent in several cancerous tissues where it appears to correlate with the degree of malignancy. Currently, TSPO is thus actively investigated as a generic biomarker for disease activity and a therapeutic target for a wide range of diseases. In this study, we report a Jurkat human T cell leukemia cell line that has only trace expression of TSPO mRNA. Through the use of bisulphite genomic sequencing, we show that the Jurkat TSPO promoter is highly methylated except for CpG sites that are adjacent to the transcription start site. Control measurements in HEK-293, HeLa, and U87-MG cells with high TSPO mRNA expression showed low levels of TSPO promoter methylation. Demethylation with 5-aza-2'-deoxycytidine (5-aza-dC) caused a dose-dependent increase in TSPO mRNA with a corresponding demethylation of the TSPO promoter in Jurkat cells. Treating HeLa and U87-MG cells with 5-aza-dC caused no change in the level of TSPO mRNA. These observations confirm the epigenetic regulation of TSPO and suggest it to be a more common mechanism by which the differential expression of TSPO in various cell types and in health and disease may be explained.

Serravalle S, Bertuccio SN, Astolfi A, et al.
Synergistic Cytotoxic Effect of L-Asparaginase Combined with Decitabine as a Demethylating Agent in Pediatric T-ALL, with Specific Epigenetic Signature.
Biomed Res Int. 2016; 2016:1985750 [PubMed] Free Access to Full Article Related Publications
T-Acute Lymphoblastic Leukemia (T-ALL) remains a subgroup of pediatric ALL, with a lower response to standard chemotherapy. Some recent studies established the fundamental role of epigenetic aberrations such as DNA hypermethylation, to influence patients' outcome and response to chemotherapy. Moreover, L-asparaginase is an important chemotherapeutic agent for treatment of ALL and resistance to this drug has been linked to ASNS expression, which can be silenced through methylation. Therefore, we tested whether the sensitivity of T-ALL cell lines towards L-asparaginase is correlated to the epigenetic status of ASNS gene and whether the sensitivity can be modified by concurrent demethylating treatment. Hence we treated different T-ALL cell lines with L-asparaginase and correlated different responses to the treatment with ASNS expression. Then we demonstrated that the ASNS expression was dependent on the methylation status of the promoter. Finally we showed that, despite the demethylating effect on the ASNS gene expression, the combined treatment with the demethylating agent Decitabine could synergistically improve the L-asparaginase sensitivity in those T-ALL cell lines characterized by hypermethylation of the ASNS gene. In conclusion, this preclinical study identified an unexpected synergistic activity of L-asparaginase and Decitabine in the subgroup of T-ALL with low ASNS expression due to hypermethylation of the ASNS promoter, while it did not restore sensitivity in the resistant cell lines characterized by higher ASNS expression.

Kanazawa Y, Yamashita Y, Fujiwara M, et al.
Two Relapsed Stage III Childhood Anaplastic Large Cell Lymphoma Patients with NPM-ALK Fusion in Bone Marrow from Initial Diagnosis.
Acta Med Okayama. 2016; 70(6):503-506 [PubMed] Related Publications
Childhood anaplastic large cell lymphoma (ALCL) accounts for approx. 10-30% of cases of non-Hodgkin lymphoma, and the ALCL99 study reported 60-75 disease-free survival; however, a relatively high relapse rate was observed (25-30% ). We report 2 patients with Stage III ALCL who relapsed 6-18 months after the end of ALCL99 chemotherapy. A retrospective molecular analysis identified the nucleophosmin (NPM)-anaplastic lymphoma kinase (ALK) fusion gene in the first diagnostic bone marrow samples taken from both patients. However, antibodies against the ALK protein appeared to be relatively low in the serum of both patients (×100 and ×750). An increase in chemotherapy intensity may be beneficial if Stage III ALCL patients are shown to be NPM-ALK chimera-positive in the first diagnostic bone marrow sample.

Hatem J, Schrank-Hacker AM, Watt CD, et al.
Marginal zone lymphoma-derived interfollicular diffuse large B-cell lymphoma harboring 20q12 chromosomal deletion and missense mutation of BIRC3 gene: a case report.
Diagn Pathol. 2016; 11(1):137 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) typically leads to effacement of the nodal architecture by an infiltrate of malignant cells. Rarely (<1%), DLBCL can present with an interfollicular pattern (DLBCL-IF) preserving the lymphoid follicles. It has been postulated that DLBCL-IF is derived from marginal zone B cells and may represent a large-cell transformation of marginal zone lymphoma (MZL), however no direct evidence has been provided to date. Here we describe a rare case of a diagnostically challenging DLBCL-IF involving a lymph node in a patient with a prior history of lymphadenopathy for several years and MZL involving skin.
CASE PRESENTATION: A 53-year old man presented to our Dermatology Clinic due to a 1-year history of generalized itching, fatigue of 2-3 month's duration, nausea and mid back rash that was biopsied. PET (positron emission tomography)/CT (computed tomography) was performed and revealed inguinal, pelvic, retroperitoneal, axillary, and cervical lymphadenopathy. The patient was referred to surgery for excisional biopsy of a right inguinal lymph node. Diagnostic H&E stained slides and ancillary studies were reviewed for the lymph node and skin specimens. B-cell clonality by PCR and sequencing studies were performed on both specimens. We demonstrate that this patient's MZL and DLBCL-IF are clonally related, strongly suggesting that transformation of MZL to DLBCL had occurred. Furthermore, we identified a novel deletion of the long arm of chromosome 20 (del(20q12)) and a missense mutation in BIRC3 (Baculoviral IAP repeat-containing protein 3) in this patient's DLBCL that are absent from his MZL, suggesting that these genetic alterations contributed to the large cell transformation.
CONCLUSIONS: To our knowledge, this is the first report providing molecular evidence for a previously suspected link between MZL and DLBCL-IF. In addition, we describe for the first time del(20q12) and a missense mutation in BIRC3 in DLBCL. Our findings also raise awareness of DLBCL-IF and discuss the diagnostic pitfalls of this rare entity.

Koehler P, Hamprecht A, Bader O, et al.
Epidemiology of invasive aspergillosis and azole resistance in patients with acute leukaemia: the SEPIA Study.
Int J Antimicrob Agents. 2017; 49(2):218-223 [PubMed] Related Publications
Invasive aspergillosis (IA) is a serious hazard to high-risk haematological patients. There are increasing reports of azole-resistant Aspergillus spp. This study assessed the epidemiology of IA and azole-resistant Aspergillus spp. in patients with acute leukaemia in Germany. A prospective multicentre cohort study was performed in German haematology/oncology centres. The incidence of probable and proven aspergillosis according to the revised EORTC/MSG criteria was assessed for all patients with acute leukaemia [acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL)]. Cases were documented into a web-based case report form, and centres provided data on standards regarding prophylactic and diagnostic measures. Clinical isolates were screened centrally for azole resistance and, if applicable, underlying resistance mechanisms were analysed. Between September 2011 and December 2013, 179 cases of IA [6 proven (3.4%) and 173 probable (96.6%)] were diagnosed in 3067 patients with acute leukaemia. The incidence of IA was 6.4% among 2440 AML patients and 3.8% among 627 ALL patients. Mortality at Day 84 was 33.8% (49/145) and attributable mortality was 26.9% (39/145). At Day 84, 53 patients (29.6%) showed a complete response, 25 (14.0%) a partial response and 17 (9.5%) a deterioration or failure. A total of 77 clinical Aspergillus fumigatus isolates were collected during the study period. Two episodes of azole-resistant IA (1.1%) were caused by a TR/L98H mutation in the cyp51A gene. With only two cases of IA due to azole-resistant A. fumigatus, a change of antifungal treatment practices in Germany does not appear warranted currently.

Cummin T, Johnson P
Lymphoma: turning biology into cures.
Clin Med (Lond). 2016; 16(Suppl 6):s125-s129 [PubMed] Related Publications
Diffuse large B-cell lymphoma (DLBCL) is the commonest aggressive non-Hodgkin lymphoma with approximately 5,000 cases annually in the UK. The R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) regimen has become the international standard of care with cure rates of around 75% and despite extensive studies aimed at improving the outcomes, R-CHOP has not been superseded. Those patients that do not respond to R-CHOP have a poor outlook. DLBCL is a disease with marked molecular heterogeneity; advances in gene expression profiling and mutational analysis can be used to increase our understanding of the disease and identify new therapeutic targets. Precision medicine using new agents, including small molecule inhibitors, is now being investigated for DLBCL. Progress in this disease is likely to come by targeting heterogeneous subtypes through novel combinations. Where R-CHOP fails, we hope that these new approaches can succeed by providing personalised medicine using precision diagnostics to guide new treatment paradigms.

Baghbani E, Baradaran B, Pak F, et al.
Suppression of protein tyrosine phosphatase PTPN22 gene induces apoptosis in T-cell leukemia cell line (Jurkat) through the AKT and ERK pathways.
Biomed Pharmacother. 2017; 86:41-47 [PubMed] Related Publications
The aim of this study was to investigate the effect of specific PTPN22 small interfering RNAs (siRNAs) on the viability and induction of apoptosis in Jurkat cells and to evaluate apoptosis signaling pathways. In this study, Jurkat cells were transfected with specific PTPN22 siRNA. Relative PTPN22 mRNA expression was measured by Quantitative Real-time PCR. Western blotting was performed to determine the protein levels of PTPN22, AKT, P-AKT, ERK, and P-ERK. The cytotoxic effects of PTPN22 siRNA were determined using the MTT assay. Apoptosis was quantified using TUNEL assay and flow cytometry. Results showed that in Jurkat cells after transfection with PTPN22 siRNA, the expression of PTPN22 in both mRNA and protein levels was effectively reduced. Moreover, siRNA transfection induced apoptosis on the viability of T-cell acute leukemia cells. More importantly, PTPN22 positively regulated the anti-apoptotic AKT kinase, which provides a powerful survival signal to T-ALL cells as well as the suppression of PTPN22 down regulated ERK activity. Our results suggest that the PTPN22 specific siRNA effectively decreases the viability of T-cell acute leukemia cells, induces apoptosis in this cell line, and therefore could be considered as a potent adjuvant in T-ALL therapy.

Olofson AM, Loo EY, Hill PA, Liu X
Plasmablastic lymphoma mimicking carcinomatosis: A case report and review of the literature.
Diagn Cytopathol. 2017; 45(3):243-246 [PubMed] Related Publications
First identified as a distinct disease entity in HIV-positive patients, plasmablastic lymphoma is a rare aggressive disease which arises predominantly in men and is associated with immunodeficiency of all causes. Although its exact etiology is poorly understood, Epstein-Barr virus infection and MYC gene aberrations have been implicated in its development in both HIV-positive and HIV-negative patients. The disease typically involves extranodal sites with a predilection for the oral cavity but may occur in other locations. Here we present a case of plasmablastic lymphoma diffusely involving the omentum and peritoneal cavity of an immunocompetent woman, clinically mimicking an ovarian carcinomatosis. To the best of our knowledge, this is the first case in which plasmablastic lymphoma has presented as peritoneal lymphomatosis. Diagn. Cytopathol. 2017;45:243-246. © 2016 Wiley Periodicals, Inc.

Karimi M, Mohammadi H, Hemmatzadeh M, et al.
Role of the HTLV-1 viral factors in the induction of apoptosis.
Biomed Pharmacother. 2017; 85:334-347 [PubMed] Related Publications
Adult T-cell leukemia (ATL) and HTLV-1-associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) are the two main diseases that are caused by the HTLV-1 virus. One of the features of HTLV-1 infection is its resistance against programmed cell death, which maintains the survival of cells to oncogenic transformation and underlies the viruses' therapeutic resistance. Two main genes by which the virus develops cancer are Tax and HBZ; playing an essential role in angiogenesis in regulating viral transcription and modulating multiple host factors as well as apoptosis pathways. Here we have reviewed by prior research how the apoptosis pathways are suppressed by the Tax and HBZ and new drugs which have been designed to deal with this suppression.

Hamadou WS, Besbes S, Mani R, et al.
ARLTS1, potential candidate gene in familial aggregation of hematological malignancies.
Bull Cancer. 2017; 104(2):123-127 [PubMed] Related Publications
INTRODUCTION: Genetic predisposition to familial hematological malignancies was previously described through several epidemiological analyses, but the genetic basis remains unclear. The tumor-suppressor ARLTS1 gene was previously described in sporadic hematological malignancies and familial cancer context.
METHODS: In this study, we sequence the ARLTS1 gene in 100 patients belonging to 88 independent Tunisian and French families.
RESULTS: After gene sequencing, we report 8 genetic variations, most of which were previously reported in several cancer forms. The most common variants were W149X and C148R and were previously associated to B-cell chronic lymphocytic leukemia and to high-risk of familial breast cancer.
CONCLUSIONS: These results emphasize the fact that ARLTS1 gene mutations can be considered as a potential predisposing factor in familial hematological malignancies and other several cancer forms.

Ejima-Yamada K, Oshiro Y, Okamura S, et al.
Epstein-Barr virus infection and gene promoter hypermethylation in rheumatoid arthritis patients with methotrexate-associated B cell lymphoproliferative disorders.
Virchows Arch. 2017; 470(2):205-215 [PubMed] Related Publications
We analyzed CpG-island hypermethylation status in 12 genes of paraffin-embedded tissues from 38 rheumatoid arthritis (RA) patients with methotrexate (MTX)-associated large B cell lymphoproliferative disorder (BLPD), 11 RA patients with non-MTX-associated BLPD (non-MTX-BLPD), 22 controls with diffuse large B cell lymphoma (DLBCL), and 10 controls with Epstein-Barr virus (EBV)(+) DLBCL. Among them, tumor cells from EBV(+) MTX-BLPD patients and control EBV(+) DLBCL patients had significantly lower median incidence of CpG island methylator phenotype (CIMP) than those from non-MTX-BLPD and control DLBCL groups (2.3 and 1.7 vs. 4.3 and 4.4; P < 0.01 for each). In the MTX-BLPD group, EBV(+) patients showed lower median CIMP than EBV(-) patients (2.3 vs. 3.2); they also had significantly lower hypermethylation incidence in four apoptosis-related genes, especially death-associated protein kinase (14 vs. 55 %), higher incidence of massive tumor necrosis (86 vs. 27 %), and lower BCL2 protein expression (19 vs. 86 %) than did the control DLBCL group (P < 0.01 for all). In all clinical stages, EBV(+) MTX-BLPD patients had better prognoses than the EBV(-) MTX-BLPD (P = 0.011), non-MTX-BLPD (P = 0.002), and control DLBCL groups (P = 0.015). MTX-BLPD patients without hypermethylated RAS-associated domain family-1A (RASSF1A) or O (6) -methyl guanine-DNA methyltransferase (MGMT) had significantly better prognosis than those with hypermethylation of those genes (P = 0.033). We conclude that in RA patients with MTX-BLPD, EBV infection is associated with a lower incidence of CIMP, apoptosis-related gene hypermethylation, and BCL2 expression, which can induce tumor regression by MTX withdrawal and lead to better prognoses.

Yang G, Deisch J, Tavares M, et al.
Primary B-cell lymphoma of the uterine cervix: Presentation in Pap-test slide and cervical biopsy.
Diagn Cytopathol. 2017; 45(3):235-238 [PubMed] Related Publications
This case involved a 69-year-old female who presented with irritative urinary voiding. Imaging studies showed an 18-cm uterine mass centering on the cervix and extending into the bladder. The Pap test slide demonstrated necrotic background and degenerative changes in single and grouped atypical "small round blue cells" with high nuclear/cytoplasm ratio, scant cytoplasm, and hyperchromatic focally cleaved nuclei with occasional nuclear membrane "snout projections." Cervical biopsies showed similar findings. The tumor cells were positive for CD45, CD20, and PAX-5, and negative with epithelial, neuroendocrine, and muscle markers. A Ki-67 immunostain showed a markedly elevated proliferative index and the MUM1 stain was diffusely positive. Molecular study identified clonal immunoglobulin heavy chain gene rearrangement. Owing to its rarity, cervical lymphoma may sometimes be confused with other types of malignant neoplasms or inflammatory processes. Therefore, it is important to recognize the cytological features of cervical lymphomas and be aware of the potential diagnostic pitfalls for timely diagnosis and therapy. Diagn. Cytopathol. 2017;45:235-238. © 2016 Wiley Periodicals, Inc.

Badar T, Srour S, Bashir Q, et al.
Predictors of inferior clinical outcome in patients with standard-risk multiple myeloma.
Eur J Haematol. 2017; 98(3):263-268 [PubMed] Related Publications
INTRODUCTION: Outcome of patients with standard-risk (SR) multiple myeloma (MM) has improved; however, subsets of patients do worse than expected. We sought to identify the factors associated with inferior outcome.
METHODS: We evaluated 51 patients with SR MM that received upfront autologous hematopoietic stem cell transplantation (auto-HCT) after induction and had a progression-free survival (PFS) of ≤18 months.
RESULTS: The median age of patients was 61 yr. Forty-one (80%) patients received induction with immunomodulatory drugs, proteosome inhibitors, or combination of both. The overall response rate (ORR) after auto-HCT was 96% (stringent complete response 23%, complete response 10%, very good partial response 22%, and partial response 39%). The median PFS was 7.8, and median overall survival (OS) was 56.3 months. On univariate analysis, concurrent light-chain amyloidosis (AL) was associated with inferior PFS [hematological response (HR); 2.51, 95% CI; 0.64-10.58, P = 0.03] and occurrence of soft tissue plasmacytoma was associated with a significantly shorter OS (HR: 3.05, 95% CI: 0.57-16.29, P = 0.02).
CONCLUSION: Our analysis suggests that concurrent AL and soft tissue plasmacytoma were associated with shorter PFS and OS, respectively. Heterogeneity in clinical outcome of SR MM merits better tools for prognostication, such as gene expression profiling and minimal residual disease assessment to identify high-risk patients.

Singh SK, Lupo PJ, Scheurer ME, et al.
A childhood acute lymphoblastic leukemia genome-wide association study identifies novel sex-specific risk variants.
Medicine (Baltimore). 2016; 95(46):e5300 [PubMed] Free Access to Full Article Related Publications
Childhood acute lymphoblastic leukemia (ALL) occurs more frequently in males. Reasons behind sex differences in childhood ALL risk are unknown. In the present genome-wide association study (GWAS), we explored the genetic basis of sex differences by comparing genotype frequencies between male and female cases in a case-only study to assess effect-modification by sex.The case-only design included 236 incident cases of childhood ALL consecutively recruited at the Texas Children's Cancer Center in Houston, Texas from 2007 to 2012. All cases were non-Hispanic whites, aged 1 to 10 years, and diagnosed with confirmed B-cell precursor ALL. Genotyping was performed using the Illumina HumanCoreExome BeadChip on the Illumina Infinium platform. Besides the top 100 statistically most significant results, results were also analyzed by the top 100 highest effect size with a nominal statistical significance (P <0.05).The statistically most significant sex-specific association (P = 4 × 10) was with the single nucleotide polymorphism (SNP) rs4813720 (RASSF2), an expression quantitative trait locus (eQTL) for RASSF2 in peripheral blood. rs4813720 is also a strong methylation QTL (meQTL) for a CpG site (cg22485289) within RASSF2 in pregnancy, at birth, childhood, and adolescence. cg22485289 is one of the hypomethylated CpG sites in ALL compared with pre-B cells. Two missense SNPs, rs12722042 and 12722039, in the HLA-DQA1 gene yielded the highest effect sizes (odds ratio [OR] ∼ 14; P <0.01) for sex-specific results. The HLA-DQA1 SNPs belong to DQA1*01 and confirmed the previously reported male-specific association with DQA1*01. This finding supports the proposed infection-related etiology in childhood ALL risk for males. Further analyses revealed that most SNPs (either direct effect or through linkage disequilibrium) were within active enhancers or active promoter regions and had regulatory effects on gene expression levels.Cumulative data suggested that RASSF2 rs4813720, which correlates with increased RASSF2 expression, may counteract the suppressor effect of estrogen-regulated miR-17-92 on RASSF2 resulting in protection in males. Given the amount of sex hormone-related mechanisms suggested by our findings, future studies should examine prenatal or early postnatal programming by sex hormones when hormone levels show a large variation.

Wyrwas M, Michel J, Guibaud I, et al.
Burkitt cells on a peripheral blood smear: how to deal with?
Ann Biol Clin (Paris). 2016; 74(6):697-703 [PubMed] Related Publications
The diagnosis of double hit lymphoma remains a challenge for the biologist for a good management of the patient. This new category of lymphoma "double hit" (DH) is part of a new entity of the WHO classification 2008: « Unclassifiable B lymphoma with features intermediate between diffuse large cell B lymphoma and Burkitt's lymphoma ». It is defined by the presence of a breakpoint at the locus 8q24 of the c-MYC gene associated with a recurrent translocation involving BCL2 genes primarily BCL6 or more rarely CCDN1 or BCL3 genes. These chromosomal alterations are not systematically screened at diagnosis, which can cause misdiagnosis and poor therapy management. These lymphomas DH have variable cytology and may be confused with Burkitt lymphoma (BL) or with diffuse large B-cell lymphoma (DLBCL). They have a very poor prognosis and are often resistant to chemotherapy. Their therapy and their prognosis are different from those of the BL or the DLBCL. This entity and its morphology as well as histology either immunophenotypic or cytogenetic characteristics must therefore be known to biologists, pathologists, and clinicians. Cooperation between the various actors in these disciplines is essential in case of atypical BL or DLBCL to lead to a precise classification of the pathology.

Jin Z, Zhou S, Zhang Y, et al.
Lycorine induces cell death in MM by suppressing Janus Kinase/signal transducer and activator of transcription via inducing the expression of SOCS1.
Biomed Pharmacother. 2016; 84:1645-1653 [PubMed] Related Publications
Despite the use of novel anti-myeloma agents,nearly all patients will eventually relapse or become refractory to drug treatment. New and more effective drugs for multiple myeloma (MM) are urgently needed. The JAK-STAT signaling pathway is important in the proliferation of myeloma cells.Lycorine,a natural alkaloid extracted from amaryllidaceae, has shown anti-tumor effects against a variety of solid tumors. However, its effects on MM remain unclear.In this study,we found that lycorine inhibited cellular viability and induced cell death in MM cell lines and primary myeloma cells which were derived from our four MM patients. The study showed that myeloma cells' cycle was being arrested under the G0/G1 phase followed by the lycorine treatment. Further mechanism analysis demonstrated that lycorine inhibited JAK2/STAT signaling through upregulation of SOCS1 in MM cells and patient MM cells.Importantly, we found that knockdown of HDAC8 resulted in increased expression of SOCS1. Collectively, our findings suggested lycorine acted as a potent novel histone deacetylase inhibitor and inhibited JAK2/STAT signaling through upregulation of SOCS1 in MM cells.

Lang T, Nie Y
MiR-148a participates in the growth of RPMI8226 multiple myeloma cells by regulating CDKN1B.
Biomed Pharmacother. 2016; 84:1967-1971 [PubMed] Related Publications
OBJECTIVE: The aim of this study is to explore the influence of miR-148a on cell proliferation and cell cycle of multiple myeloma (MM) cell line RPMI8226 and the related molecular mechanism.
METHODS: The expression of miR-148a and CDKN1B in MM cells and primary cells of normal bone marrow were determined by RT-PCR and western blotting. The cell proliferation and cell cycle of miR-148a knockdown MM cells and normal MM cells were determined by flow cytometry. The protein expression of p-NPAT, p-Rb and p-CDC6 was determined in normal and miR-148a knockdown MM cells. Luciferase reported assay was used to explore the relationship between miR-148a and CDKN1B.
RESULTS: The level of miR-148a in MM cells was much higher than that in primary cells from healthy bone marrow samples, while the expression of CDKN1B was lower in MM cells. After knockdown of miR-148a, cell cycle mainly distributed at G0/G1 and the proliferation capacity of MM cells decreased. Knockdown of miR-148a significantly reduced protein expression of p-NPAT, p-Rb and p-CDC6. Luciferase reported assay showed that miR-148a could directly target CDKN1B at 3'-UTR.
CONCLUSIONS: High level of miR-148a inhibits CDK activity and promotes the proliferation of MM cells at least partly by downregulating CDKN1B.

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