Your Cancer-Immunity Cycle within Multiple Myeloma.
 CTCF is a key regulator of gene expression through organization of the chromatin structure. Still, it is unclear how CTCF binding is perturbed in leukemia or in cancer in general.  https://www.selleckchem.com/products/OSI-906.html  We studied CTCF binding by ChIP-Seq in cells from patients with acute myeloid leukemia (AML) and in normal bone marrow (NBM) in the context of gene expression, DNA methylation and azacytidine exposure. CTCF binding was increased in AML compared to NBM. Aberrant CTCF binding was enriched for motifs for key myeloid transcription factors such as CEBPA, PU.1 and RUNX1. AML with TET2 mutations was characterized by a particularly strong gain of CTCF binding, highly enriched for gain in promoter regions while AML in general was enriched for changes at enhancers. There was a strong anti-correlation between CTCF binding and DNA methylation. Gain of CTCF occupancy was associated with increased gene expression, however, the genomic location (promoter vs. distal regions) and enrichment of motifs (for repressing vs. activating co-factors) were decisive for the gene expression pattern. Knock-down of CTCF in K562 cells caused loss of CTCF binding and transcriptional repression of genes with changed CTCF binding in AML, as well as loss of RUNX1 binding at RUNX1/CTCF binding sites. In addition, CTCF knock-down caused increased differentiation. Azacytidine exposure caused major changes in CTCF occupancy in AML patient cells, partly by restoring a CTCF binding pattern similar to NBM.  https://www.selleckchem.com/products/OSI-906.html  We conclude that AML displays an aberrant increase in CTCF occupancy that targets key genes for AML development and impacts on gene expression. Copyright © 2020 American Society of Hematology.Current objectives regarding treatment for acute myeloid leukemia (AML) include achieving complete remission (CR) by clinicopathological criteria followed by interrogation for the presence of minimal/measurable residual disease (MRD) by molecular genetic and/or flow cytometric techniques. While advances in molecular genetic technologies have enabled highly sensitive detection of AML-associated mutations and translocations, determination of MRD is complicated by the fact that many treated patients have persistent clonal hematopoiesis that may not reflect residual AML. Clonal hematopoiesis detected in AML patients in CR includes true residual or early recurrent AML, myelodysplastic syndrome (MDS) or clonal hematopoiesis that is ancestral to the AML, and independent or newly emerging clones of uncertain leukemogenic potential. While the presence of AML-related mutations has been shown to be a harbinger of relapse in multiple studies, the significance of other types of clonal hematopoiesis is less well understood. In patients who undergo allogeneic hematopoietic cell transplantation (HCT), post-HCT clones can be donor-derived and in some cases engender a new myeloid neoplasm that is clonally unrelated to the recipient's original AML. In this article, we discuss the spectrum of clonal hematopoiesis that can be detected in treated AML patients, propose terminology to standardize nomenclature in this setting, and review clinical data and areas of uncertainty among the various type of post-treatment hematopoietic clones. Copyright © 2020 American Society of Hematology.A goal in precision medicine is to use patient-derived material to predict disease course and intervention outcomes. Here, we use mechanistic observations in a preclinical animal model to design an ex vivo platform that recreates genetic susceptibility to T cell-mediated damage. Intestinal graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT). We found that intestinal GVHD in mice deficient in Atg16L1, an autophagy gene that is polymorphic in humans, is reversed by inhibiting necroptosis. We further show that co-cultured allogeneic T cells kill Atg16L1 mutant intestinal organoids from mice, which was associated with an aberrant epithelial interferon signature. Using this information, we demonstrate that pharmacologically inhibiting necroptosis or interferon signaling protects human organoids derived from individuals harboring a common ATG16L1 variant from allogeneic T cell attack. Our study provides a roadmap for applying findings in animal models to individualized therapy that targets affected tissues. Copyright © 2020 American Society of Hematology.Great heterogeneity in survival exists for patients newly diagnosed with DLBCL. Three scoring systems incorporating simple clinical parameters (age, lactate dehydrogenase, number/sites of involvement, stage, performance status) are widely used the international prognostic index (IPI), revised-IPI (R-IPI), and National Comprehensive Cancer Network IPI (NCCN-IPI). We evaluated 2124 DLBCL patients treated from 1998 to 2009 with front-line R-CHOP (or variant) across 7 multicenter randomized clinical trials to determine which scoring system best discriminates overall survival (OS). Median age was 63 years and 56% of patients were male. Five-year OS estimates ranged from 54% to 88%, 61% to 93%, and 49% to 92% using the IPI, R-IPI, or NCCN-IPI, respectively. The NCCN-IPI had the greatest absolute difference in OS estimates between the highest and lowest risk groups and best discriminated OS (c-index = 0.632 vs. 0.626 (IPI) vs. 0.590 (R-IPI)). For each given IPI risk category, NCCN-IPI risk categories were significantly associated with OS (P less then 0.01); the reverse was not true and the IPI did not provide additional significant prognostic information within all NCCN-IPI risk categories. Collectively, the NCCN-IPI outperformed the IPI and R-IPI. Patients with low NCCN-IPI had favorable survival outcomes with little space for further improvement. In the rituximab era, none of the clinical risk scores identified a patient subgroup with long-term survival clearly below 50%. Integrating molecular features of the tumor and microenvironment into NCCN-IPI or IPI might better characterize a high risk group where novel treatment approaches are most needed. Copyright © 2020 American Society of Hematology.As part of a randomized, prospective clinical trial in large cell lymphoma, we conducted serial FDG-PET at baseline, after two cycles of chemotherapy (i-PET), and at end of treatment (EoT) to identify biomarkers of response that are predictive of remission and survival. Scans were interpreted in a core laboratory by two imaging experts, using the visual 5-point scale (5-PS), and by calculating percent change in FDG uptake (ΔSUV). Visual scores of 1-3 and ΔSUV ≥ 66% were prospectively defined as negative. Of 524 patients enrolled in the parent trial, 169 agreed to enroll in the PET substudy and 158 were eligible for final analysis. In this selected population, all had FDG-avid disease at baseline; by 5-PS, 55 (35%) remained positive on i-PET and 28 (18%) on EoT PET. Median ΔSUV on i-PET was 86.2%. With a median follow-up of 5 years, ΔSUV, as continuous variable, was associated with progression-free survival (PFS) (HR=0.99, 95% CI 0.97-1.00, p=0.02) and overall survival (OS) (HR=0.98, 95% CI 0.97-0.99, p=0.03).