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Identifying the central transcription factors (TF) and regulatory genomic elements that control oncogenic transcriptional programs may be key to designing targeted therapeutics that interrupt these tumor-promoting genetic networks. In patients with acute myeloid leukemia (AML), loss of MHCII expression on malignant cells is associated with relapse following hematopoietic stem cell transplant, but the regulatory factors responsible remain unknown. On page [394], Eagle and colleagues present CORENODE, an algorithm that infers TF/target gene relationships from transcriptional profiles, and identified four key regulatory TFs of MHCII in AML blasts—MYB, MEIS1, IRF8, and MEF2C—independent of canonical CIITA regulation. Subpopulations of AML cells with altered expression of these TFs were found in pre-relapse patient samples, suggestive of preexisting relapse-driving populations. This work demonstrates the ability to identify central, and potentially targetable, TF drivers of disease through novel analytical methods. - PDF Icon PDF LinkTable of Contents
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Research Brief
Clonal Hematopoiesis Is Associated with Increased Risk of Severe Neurotoxicity in Axicabtagene Ciloleucel Therapy of Large B-Cell Lymphoma
Clonal hematopoiesis (CH) is associated with increased risk of CAR T cell–related inflammatory toxicities in patients with B-cell lymphoma, especially in CH driven by mutations in DNMT3A, TET2, or ASXL1.
Research Articles
Transcriptional Plasticity Drives Leukemia Immune Escape
CORENODE, a computational network decomposition algorithm, identifies an adaptive transcriptional mechanism of leukemia immune escape through combinatorial fluctuations of transcription factor expression.
Amplified EPOR/JAK2 Genes Define a Unique Subtype of Acute Erythroid Leukemia
Amplified EPOR/JAK2 with multi-hit TP53 lesions define a unique subtype of AEL showing extreme erythroid differentiation with activated STAT5 and aggressive clinical courses, for which a potential therapeutic role of JAK2 inhibition is suggested.
Follicular Lymphoma Microenvironment Characteristics Associated with Tumor Cell Mutations and MHC Class II Expression
Han and Deng et al. show the relationship between follicular lymphoma tumor B-cell mutations and expression patterns, and associations with characteristics of tumor-infiltrating T-cell subsets.
PU.1-Dependent Enhancer Inhibition Separates Tet2-Deficient Hematopoiesis from Malignant Transformation
Moderate deregulation of PU.1 can trigger malignant transformation of Tet2-deficient stem cells through epigenetic inactivation of a methylation sensitive PU.1 binding motif controlling a key myeloid differentiation program.
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