Blood

Cohesin complex disruption alters gene expression and Cohesin mutations are common in myeloid neoplasia, suggesting a critical role in hematopoiesis. Here, we explore Cohesin dynamics and regulation of hematopoietic stem cell homeostasis and differentiation. Cohesin binding increases at active regulatory elements only during erythroid differentiation. Prior binding of the repressive Ets transcription factor Etv6 predicts Cohesin binding at these elements and Etv6 interacts with Cohesin at chromatin. Depletion of Cohesin severely impairs erythroid differentiation, particularly at Etv6-pre-bound loci, but augments self-renewal programmes...

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Leukemia stem cells are a rare population with a primitive progenitor phenotype that can initiate, sustain, and recapitulate leukemia through a poorly understood mechanism of self-renewal. Here, we report that KLF4 promotes disease progression in a murine model of chronic myeloid leukemia (CML)-like myeloproliferative neoplasia by repressing an inhibitory mechanism of preservation in leukemia stem/progenitor cells with leukemia-initiating capacity. Deletion of the Klf4 gene severely abrogated the maintenance of BCR-ABL1(p210)-induced CML by impairing survival and self-renewal in BCR-ABL1+ CD150+ LSK leukemic cells...

Prior studies have reported high response rates with recombinant interferon-α (rIFN-α) therapy in patients with essential thrombocythemia (ET) and polycythemia vera (PV). To further define the role of rIFN-α, we investigated the outcomes of pegylated-rIFN-α2a (PEG) therapy in patients with ET/PV previously treated with hydroxyurea (HU). The Myeloproliferative Disorders Research Consortium (MPD-RC) 111 study was an investigator-initiated, international, multicenter, phase 2 trial evaluating the ability of PEG therapy to induce complete (CR) and partial (PR) hematologic responses in patients with high-risk ET/PV who were either refractory or intolerant to HU...

Mycosis fungoides (MF) is a mature T-cell lymphoma currently thought to develop primarily in the skin by a clonal expansion of a transformed, resident memory T-cell. However, this concept does not explain the key characteristics of MF such as the debut with multiple, widespread skin lesions or inability of skin directed therapies to provide cure. The testable inference of the mature T-cell theory is the clonality of MF with respect to all rearranged T-cell receptor (TCR) genes. Here we have used whole exome sequencing approach to detect and quantify TCRα, -β and -γ clonotypes in tumor cell clusters microdissected from MF lesions...

Chronic myeloid leukemia (CML) is rare in children and accounts for {less than or equal to} 15% of all myeloid leukemia cases. When we initiated this study with nilotinib, imatinib was the only tyrosine kinase inhibitor indicated for pediatric patients with Philadelphia chromosome-positive (Ph+) CML in chronic phase (CP); alternative treatment options were needed, particularly for patients who developed resistance/intolerance (R/I) to imatinib. This phase 2 study enrolled pediatric patients with either Ph+ CML-CP R/I to imatinib/dasatinib or newly diagnosed Ph+ CML-CP...

Increased energy requirement and metabolic reprograming are hallmarks of cancer cells. We show that metabolic alterations in hematopoietic cells are fundamental to the pathogenesis of mutant JAK2 driven myeloproliferative neoplasms (MPNs). We found that expression of mutant JAK2 augmented and subverted metabolic activity of MPN cells resulting in systemic metabolic changes in vivo, including hypoglycemia, adipose tissue atrophy and early mortality. Hypoglycemia in MPN mouse models correlated with hyperactive erythropoiesis and was due to a combination of elevated glycolysis and increased oxidative phosphorylation...

Fluid shear stress in the vasculature is the driving force for natural bypass growth, a fundamental endogenous mechanism to counteract the detrimental consequences of vascular occlusive disease such as stroke or myocardial infarction. This process referred to as arteriogenesis relies on local recruitment of leukocytes, which supply growth factors to pre-existing collateral arterioles enabling them to grow. Although several mechanosensing proteins have been identified, the series of mechanotransduction events resulting in local leukocyte recruitment are not understood...

We investigated and modelled the mesenchymal stromal cell (MSC) niche in adult acute lymphoblastic leukaemia (ALL). We used gene expression profiling, cytokine/chemokine quantification, flow cytometry and a variety of imaging techniques to show that MSC directly isolated from the primary bone marrow specimens of patients with ALL frequently adopted an activated, cancer-associated fibroblast phenotype. Normal, primary human MSC and the MSC cell line HS27a both became activated de novo, when exposed to the reactive oxygen species (ROS)-inducing chemotherapy agents cytarabine (AraC) and daunorubicin (DNR), a phenomenon blocked by the anti-oxidant N-acetyl cysteine...

Dysregulated immune responses are essential underlying causes of a plethora of pathologies including cancer, autoimmunity and immunodeficiency. We here investigated four patients from unrelated families presenting with immunodeficiency, autoimmunity, and malignancy. We identified four distinct homozygous mutations in TNFRSF9 encoding the Tumor Necrosis Factor superfamily member CD137/4-1BB, leading to reduced or loss of protein expression. Lymphocytic responses crucial for immune surveillance, including activation, proliferation, and differentiation, were impaired...

The PRC2 complex, with core components EZH2, SUZ12 and EED, is responsible for writing H3K27me3 histone marks associated with gene repression. Analysis of sequence data from 419 T-cell acute lymphoblastic leukemia (T-ALL) cases demonstrated a significant association between SUZ12 and JAK3 mutations. Here we show that CRISPR/Cas9-mediated inactivation of Suz12 cooperates with mutant JAK3 to drive T-cell transformation and T-ALL development. Gene expression profiling integrated with ChIP-seq and ATAC-seq data established that inactivation of Suz12 led to increased PI3K/mTOR, VEGF and WNT signaling...

Venetoclax in combination with obinutuzumab is an efficacious and tolerable combination that provides a fixed-duration, chemotherapy-free option for patients with previously untreated chronic lymphocytic leukemia (CLL). With the expanding number of therapeutic alternatives available for CLL, discussion of efficacy and potential adverse effects are paramount to formulating the optimal treatment regimen for each individual patient. Many ongoing studies will further define the ideal combination and long-term efficacy of these novel therapies in a prospective manner...

Germline DDX41 mutations are involved in familial myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML). We analyzed the prevalence and characteristics of DDX41 -related myeloid malignancies in an unselected cohort of 1385 patients with MDS or AML. Using targeted next-generation sequencing, we identified 28 different germline DDX41 variants in 43 unrelated patients which we classified as causal (n=21) or unknown significance (n=7) variants. We focused on the 33 patients having causal variants, representing 2...

Achieving and maintaining high-quality response is the treatment goal for patients with newly diagnosed multiple myeloma (NDMM). The phase 3 PETHEMA/GEM2012 study, in 458 patients {less than or equal to} 65 years old with NDMM, is evaluating bortezomib (subcutaneous) + lenalidomide + dexamethasone (VRD) for 6 cycles followed by autologous stem cell transplant (ASCT) conditioned with intravenous busulfan + melphalan vs melphalan and posttransplant consolidation with 2 cycles of VRD. We present grouped response analysis of induction, transplant, and consolidation...

Clinical observations implicate a role of eosinophils in cardiovascular diseases, because markers of eosinophils activation are elevated in atherosclerosis and thrombosis. However, their contribution to atherosclerotic plaque formation and arterial thrombosis remains unclear. In these settings, we investigated how eosinophils are recruited and activated through an interplay with platelets. Here, we provide evidence for a central importance of eosinophil-platelet interactions in atherosclerosis and thrombosis...

The peripheral T-cell lymphoma (PTCL) are uniquely sensitive to epigenetic modifiers. Based on the synergism between histone deacetylase (HDAC) inhibitors and hypomethylating agents we established in preclinical PTCL models, we conducted a phase 1 study of oral 5-azacytidine (AZA) and romidepsin (ROMI) in patients with advanced lymphoid malignancies, with emphasis on PTCL. Following a 3 + 3 design patients were assigned to one of seven cohorts with AZA doses ranging from 100 mg daily on days 1-14 to 300 mg daily on days 1-21, ROMI doses ranging from 10 mg/m2 on days 8 and 15, to 14 mg/m2 on days 8, 15, and 22, and cycles of 21 to 35 days...

Filamins (FLNs) are large dimeric actin binding proteins regulating actin cytoskeleton remodeling. In addition FLNs serve as scaffolds for signaling proteins such as tyrosine kinases, GTPases or phosphatases, as well as for adhesive receptors such as integrins. They thus connect adhesive receptors to signaling pathways and to cytoskeleton. There are 3 isoforms of FLNs (FLNa, FLNb, FLNc) originating from 3 homologous genes. FLNa has been the recent focus of attention because its mutations are responsible for a wide spectrum of defects, called filaminopathies A, affecting brain (peri-ventricular nodular heterotopia or PVNH), heart (valve defect), skeleton, gastro-intestinal tract or more recently, the megakaryocytic lineage...

Beta-thalassemia and sickle cell disease (SCD) are the most prevalent monogenic diseases. These disorders are caused by quantitative or qualitative defects in the production of adult hemoglobin. Gene therapy is a potential treatment option for patients lacking an allogenic compatible hematopoietic stem cell (HSC) donor. The generation of lentiviral vectors (LVs) carrying a β-globin-like gene has revolutionized this field by allowing effective HSC transduction with no evidence of genotoxicity to date. Several clinical trials with different kinds of vector are underway worldwide; the initial results are promising with regard to sustained production of therapeutic hemoglobin, improved biological parameters, lower transfusion requirement and better quality of life...

Extracorporeal photopheresis (ECP) has demonstrated therapeutic benefit in patients with Sézary Syndrome (SS) and erythrodermic mycosis fungoides (MF). To examine the efficacy of ECP in the modern era of novel therapies, we conducted a retrospective analysis of 65 patients with a diagnosis of SS or erythrodermic MF with blood involvement who were treated with ECP at our institute. Overall survival (OS) and time-to-next-treatment (TTNT) were used as the study endpoints to determine patient outcome. The median follow-up from diagnosis was 48 months (range 1-225 months), with a median predicted OS of 120 months...

DNA methylation has pivotal regulatory roles in mammalian development, retrotransposon silencing, genomic imprinting, X-chromosome inactivation and cancer. Cancer cells display highly dysregulated DNA methylation profiles characterized by global hypomethylation in conjunction with hypermethylation of promoter CpG islands (CGIs); these changes are often correlated with promoter hypermethylation leading to decreased expression of tumor suppressor genes, as well as with genome instability leading to amplification and aberrant expression of oncogenes...