We report the discovery of the GATA2 gene as a new myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) predisposition gene. We found the same, novel heterozygous c.1061C>T (p.Thr354Met) missense mutation in the GATA2 transcription factor gene segregating with the multigenerational transmission of MDS/AML in three families, and a GATA2 c.1063_1065delACA (p.Thr355del) mutation at an adjacent codon in a fourth MDS/AML family. The mutations reside within the second zinc finger of GATA2 which mediates DNA-binding and protein-protein interactions. We show differential effects of the mutants on transactivation of target genes, cellular differentiation, apoptosis and global gene expression. Identification of such predisposing genes to familial forms of MDS and AML is critical for more effective diagnosis and prognosis, counselling, selection of related bone marrow transplant donors, and development of therapies.

Ecotropic viral integration site 1 (EVI1) is an oncogenic dual domain zinc finger transcription factor that plays an essential role in the regulation of hematopoietic stem cell renewal, and its overexpression in myeloid leukemia and epithelial cancers is associated with poor patient survival. Despite the discovery of EVI1 in 1988 and its emerging role as a dominant oncogene in various types of cancer, few EVI1 target genes are known. This lack of knowledge has precluded a clear understanding of exactly how EVI1 contributes to cancer. Using a combination of ChIP-Seq and microarray studies in human ovarian carcinoma cells, we show that the two zinc finger domains of EVI1 bind to DNA independently and regulate different sets of target genes. Strikingly, an enriched fraction of EVI1 target genes are cancer genes or genes associated with cancer. We also show that more than 25% of EVI1-occupied genes contain linked EVI1 and activator protein (AP)1 DNA binding sites, and this finding provides evidence for a synergistic cooperative interaction between EVI1 and the AP1 family member FOS in the regulation of cell adhesion, proliferation, and colony formation. An increased number of dual EVI1/AP1 target genes are also differentially regulated in late-stage ovarian carcinomas, further confirming the importance of the functional cooperation between EVI1 and FOS. Collectively, our data indicate that EVI1 is a multipurpose transcription factor that synergizes with FOS in invasive tumors. E cotropic viral integration site 1 (EVI1) is a zinc finger (ZNF) transcription factor (TF), and its overexpression in myeloid leukemia (1-3) and epithelial cancers (1, 2, 4-9) has been extensively studied and correlated with adverse patient outcome (7, 10, 11). EVI1 also controls several aspects of embryonic development, including hematopoiesis, angiogenesis, and heart and neural development (12). Three major alternative splice forms of the MDS1 and EVI1 complex locus (MECOM) locus have been identified, including EVI1, EVI1Δ324, and MDS1-EVI1. The PRDI-BF1 and RIZ homology domain containing Myelodysplastic syndrome (MDS)1-EVI1 isoform acts as a tumor suppressor gene, whereas the shorter isoforms, EVI1 and EVI1Δ324, that lack this domain display oncogenic functions (13). The most oncogenic isoform, EVI1, encodes a 1,051-aa protein containing two DNA binding ZNF domains of seven and three motifs. The N-terminal ZNF domain binds to a GATA-like consensus motif (14), whereas the distal ZNF domain binds to an v-ets erythroblastosis virus E26 oncogene homolog (ETS)-like motif (15). EVI1Δ324 lacks ZNFs motifs 6 and 7, which prevents its binding to GATA-like sites.Despite its discovery in 1988 (16, 17), very few EVI1 target genes have been identified, and most of these loci are known to be bound by EVI1 . This lack of knowledge regarding the genes transcriptionally regulated by EVI1 has precluded a complete understanding of EVI1's role in development and cancer. In general, these biological processes are triggered by gene expression changes coordinate...

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Multiple myeloma (MM), a hematological malignancy characterized by the clonal growth of malignant plasma cells (PCs) in the bone marrow, is preceded by the benign asymptomatic condition, monoclonal gammopathy of undetermined significance (MGUS). Several genetic abnormalities have been identified as critical for the development of MM; however, a number of these abnormalities are also found in patients with MGUS, indicating that there are other, as yet unidentified, factors that contribute to the onset of MM disease. In this study, we identify a Samsn1 gene deletion in the 5TGM1/C57BL/KaLwRij murine model of myeloma. In addition, SAMSN1 expression is reduced in the malignant CD138 + PCs of patients with MM and this reduced expression correlates to total PC burden. We identify promoter methylation as a potential mechanism through which SAMSN1 expression is modulated in human myeloma cell lines. Notably, re-expression of Samsn1 in the 5TGM1 murine PC line resulted in complete inhibition of MM disease development in vivo and decreased proliferation in stromal cell–PC co-cultures in vitro. This is the first study to identify deletion of a key gene in the C57BL/KaLwRij mice that also displays reduced gene expression in patients with MM and is therefore likely to play an integral role in MM disease development.

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Importantly, this report contributes to a better overview of the incidence of EP300-ZNF384 patients and show that they have a distinct gene signature with concurrent up-regulation of JAK-STAT pathway, reduced expression of B-cell regulators and reduced DNA repair capacity.

Summary There is currently no biomarker that reliably predicts treatment‐free remission (TFR) in chronic myeloid leukaemia (CML). We characterised effector and suppressor immune responses at the time of tyrosine kinase inhibitor (TKI) cessation in patients from the CML8 and CML10 clinical studies. Natural killer (NK) cells with increased expression of activating NK receptors were higher in patients who achieved TFR. There was no difference in the proportion of CD4+ or CD8+ T cells. Furthermore, we found that FoxP3+ regulatory T cells (T reg) and monocytic myeloid‐derived suppressor cells (Mo‐MDSCs) were concomitantly decreased in TFR patients, suggesting that the effector and suppressor arms of the immune system work in concert to mediate TFR. A discovery cohort (CML10) was used to generate a predictive model, using logistic regression. Patients classified into the high‐risk group were more likely to relapse when compared with the low‐risk group (HR 7·4, 95% CI 2·9‐19·1). The model was successfully validated on the independent CML8 cohort (HR 8·3, 95% CI 2·2–31·3). Effective prediction of TFR success may be obtained with an effector‐suppressor score, calculated using absolute NK cell, T reg, and Mo‐MDSC counts, at TKI cessation, reflecting the contribution of both immune suppressors and effectors in the immunobiology underlying successful TFR.