Cohesin Members Stag1 and Stag2 Display Distinct Roles in Chromatin Accessibility and Topological Control of HSC Self-Renewal and Differentiation

Transcriptional regulators, including the cohesin complex member STAG2, are recurrently mutated in cancer. The role of STAG2 in gene regulation, hematopoiesis, and tumor suppression remains unresolved. We show that Stag2 deletion in hematopoietic stem and progenitor cells (HSPCs) results in altered hematopoietic function, increased self-renewal, and impaired differentiation. Chromatin immunoprecipitation (ChIP) sequencing revealed that, although Stag2 and Stag1 bind a shared set of genomic loci, a component of Stag2 binding sites is unoccupied by Stag1, even in Stag2-deficient HSPCs. Although concurrent loss of Stag2 and Stag1 abrogated hematopoiesis, Stag2 loss alone decreased chromatin accessibility and transcription of lineage-specification genes, including Ebf1 and Pax5, leading to increased self-renewal and reduced HSPC commitment to the B cell lineage. Our data illustrate a role for Stag2 in transformation and transcriptional dysregulation distinct from its shared role with Stag1 in chromosomal segregation

A Case of Familial Mediterranean Fever with Extensive Lymphadenopathy and Complex Heterozygous Genotype Presenting in the Fourth Decade

Familial Mediterranean fever (FMF) is an inherited disease caused by loss of function mutations in the MEFV gene encoding pyrin, a negative regulator of interleukin-1. The disease is characterized by recurrent fever and self-limited attacks of joint, chest, and abdominal pain but lymphadenopathy is an infrequent manifestation. While mesenteric lymphadenopathy has been described in several cases in the literature; hilar, paratracheal, axillary, pelvic, and retroperitoneal lymphadenopathy are extremely rare and have been reported separately in very few individuals. In this report, we present a patient with late-onset FMF with extensive lymphadenopathy in all of the aforementioned anatomic regions. Genetic analysis identified three heterozygous pyrin mutations in a patient with no affected family members. Genetic investigation of the patient’s mother identified a novel carrier haplotype E148Q/P369S. The proband also inherited the previously described and rare A744S mutation previously not thought to be a disease-defining lesion. This unique compound heterozygous genotype resulted in a novel genotype-phenotype association producing an atypical clinical presentation of FMF that fits within the pattern of several case reports of late-onset disease with respect to clinical course and therapeutic response

MICA Polymorphism Identified by Whole Genome Array Constitutes a Disease Predisposition Factor in T-Cell Large Granular Lymphocyte Leukemia

Abstract Large granular lymphocyte leukemia (LGL) is a disease of semiautonomous proliferation of cytotoxic T-cells (CTL) often accompanied by immune cytopenias, particularly neutropenia. LGL related cytopenias have been attributed to LGL cellular cytotoxicity or proapoptotic cytokines rather than intrinsic properties of the neutrophils. The association of LGL with autoimmunity suggests that genetic predisposition may contribute to disease pathogenesis. We studied 69 patients with LGL leukemia using a case-control approach; control populations included ethnically matched healthy individuals (N=82) and disease controls of aplastic anemia (N=48) and kidney transplant recipients (N=48). Initially, we applied the Illumina 12K non-synonymous SNP array to a subcohort of 36 LGL patients and 54 healthy controls (training set). Results were subjected to independent hypothesis-generating biostatistical algorithms. First, Exemplar automated analysis determined disease prediction based on independent χ2 analysis for each SNP. As expected, no SNP in this underpowered study reached Bonferroni corrected statistical significance, but our analysis allowed for ranking based on p-value. Second, Random Forests, a nonparametric tree method was applied, whereby all SNP information was calculated multivariately to predict disease. In a non-Mendelian inherited disease, this method more closely reflects the biology of complex polygenic traits; remarkably, those SNP identified by Random Forest were among the highest ranking SNP by Exemplar. Our initial hypothesis-generating set identified 1 SNP in unknown gene C8orf31 and 4 SNP within the MHC class I related-chain A (MICA) gene. We focused on MICA, a non-peptide presenting, tightly regulated stress response HLA molecule that could play a role in pathogenesis of neutropenia in LGL. To further substantiate our finding, the initial training set results were subjected to technical validation; fidelity was rechecked by PCR genotyping with 93% concordance. Biological validation was determined by confirmation in an independent test set consisting of 33 LGL patients and additional 28 controls. As only limited numbers of SNP were tested, there was no need for α-error adjustment. MICA SNP rs1063635 was found to have the most predictive value in both the training set (PPV=56%, NPV=89%) and test set (PPV=64%, NPV=86%). Overall, the control frequency of this SNP in homozygous form was 12% vs 60% in LGL (p<.01, OR=9.1). MICA alleles have been implicated in autoimmune diseases and malignancies. Although this SNP may not define a particular MICA genotype, it is possible that it is in linkage disequilibrium with genotype-defining polymorphisms. To study the functional consequences of our findings, flow cytometric analysis using anti-MICA antibodies was performed, which identified higher expression of MICA in neutrophils from patients as compared to controls (p=.04). MICA overexpression decreased after immunosuppressive therapy (p<.01). While the mechanism of MICA induction is unknown, we stipulate that the presence of MICA alleles leads to a persistent stimulatory signal in LGL predisposing to clonal outgrowth. In sum, our findings suggest that MICA polymorphisms may represent a predisposition factor in LGL and/or LGL-associated neutropenia

Racial disparities in the survival of American children, adolescents, and young adults with acute lymphoblastic leukemia, acute myelogenous leukemia, and Hodgkin lymphoma.

BackgroundRace-based survival in children and adolescents with hematologic malignancies has been a national challenge for decades. Large-scale investigations of age- and race-based survival trends over time in these patients have not previously been reported. The objective of this study was to investigate whether race- and age-related differences in pediatric and adolescent and young adult (AYA) leukemia and lymphoma survival persist and to what extent these differences have changed over time.MethodsUsing the Surveillance, Epidemiology, and End Results program, this study investigated the outcomes of black and white (1975-2012; n = 27,369) and white and Hispanic (1992-2012; n = 20,574) children (0-14 years old) and AYAs (15-39 years old) with acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and Hodgkin lymphoma (HL). Estimates of 5- and 10-year relative survival were compared over time.ResultsTrends showed a convergence of survival for white and black children with ALL but a divergence in survival for AYA patients. Hispanic children and AYAs both suffered inferior outcomes. Trends for AML revealed persistent survival differences between black and white children and suggested worsening disparities for AYAs. Survival trends in HL revealed sustained survival differences between black and white AYA patients, whereas no differences were found in Hispanic and white patient outcomes for AML or HL.ConclusionsAlthough survival for children and AYAs with ALL, AML, and HL has improved over the past 4 decades, differences persist between black, white, and Hispanic children and AYAs; survival disparities between black and white children with ALL have been nearly eliminated. Strategies aimed at identifying causality and reducing disparities are warranted. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2723-2730. © 2016 American Cancer Society

Racial disparities in the survival of American children, adolescents, and young adults with acute lymphoblastic leukemia, acute myelogenous leukemia, and Hodgkin lymphoma.

BACKGROUND: Race-based survival in children and adolescents with hematologic malignancies has been a national challenge for decades. Large-scale investigations of age- and race-based survival trends over time in these patients have not previously been reported. The objective of this study was to investigate whether race- and age-related differences in pediatric and adolescent and young adult (AYA) leukemia and lymphoma survival persist and to what extent these differences have changed over time. METHODS: Using the Surveillance, Epidemiology, and End Results program, this study investigated the outcomes of black and white (1975-2012; n = 27,369) and white and Hispanic (1992-2012; n = 20,574) children (0-14 years old) and AYAs (15-39 years old) with acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and Hodgkin lymphoma (HL). Estimates of 5- and 10-year relative survival were compared over time. RESULTS: Trends showed a convergence of survival for white and black children with ALL but a divergence in survival for AYA patients. Hispanic children and AYAs both suffered inferior outcomes. Trends for AML revealed persistent survival differences between black and white children and suggested worsening disparities for AYAs. Survival trends in HL revealed sustained survival differences between black and white AYA patients, whereas no differences were found in Hispanic and white patient outcomes for AML or HL. CONCLUSIONS: Although survival for children and AYAs with ALL, AML, and HL has improved over the past 4 decades, differences persist between black, white, and Hispanic children and AYAs; survival disparities between black and white children with ALL have been nearly eliminated. Strategies aimed at identifying causality and reducing disparities are warranted. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2723-2730. © 2016 American Cancer Society

Genetic alterations of the cohesin complex genes in myeloid malignancies

Somatic cohesin mutations have been reported in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). To account for the morphologic and cytogenetic diversity of these neoplasms, a well-annotated cohort of 1060 patients with myeloid malignancies including MDS (n = 386), myeloproliferative neoplasms (MPNs) (n = 55), MDS/MPNs (n = 169), and AML (n = 450) were analyzed for cohesin gene mutational status, gene expression, and therapeutic and survival outcomes. Somatic cohesin defects were detected in 12% of patients with myeloid malignancies, whereas low expression of these genes was present in an additional 15% of patients. Mutations of cohesin genes were mutually exclusive and mostly resulted in predicted loss of function. Patients with low cohesin gene expression showed similar expression signatures as those with somatic cohesin mutations. Cross-sectional deep-sequencing analysis for clonal hierarchy demonstrated STAG2, SMC3, and RAD21 mutations to be ancestral in 18%, 18%, and 47% of cases, respectively, and each expanded to clonal dominance concordant with disease transformation. Cohesin mutations were significantly associated with RUNX1, Ras-family oncogenes, and BCOR and ASXL1 mutations and were most prevalent in high-risk MDS and secondary AML. Cohesin defects were associated with poor overall survival (27.2 vs 40 months; P = .023), especially in STAG2 mutant MDS patients surviving >12 months (median survival 35 vs 50 months; P = .017)