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TET2inactivating mutations serve as initiating genetic lesions in the transformation of hematopoietic stem and progenitor cells (HSPCs). In this study, we analyzed known drugs in zebrafish embryos for their abilities to selectively killtet2-mutant HSPCsin vivo, and we found that the exportin 1 (XPO1) inhibitors, selinexor and eltanexor, selectively killtet2-mutant HSPCs. In serial replating colony assays, these small molecules were selectively active in killing murineTet2-deficient Lineage-, Sca1+, Kit+ (LSK) cells, and alsoTET2-inactivated human acute myeloid leukemia (AML) cells. Selective killing ofTET2-mutant HSPCs and human AML cells by these inhibitors was due to increased levels of apoptosis, without evidence of DNA damage based on increased γH2AX expression. The finding thatTET2loss renders HSPCs and AML cells selectively susceptible to cell death induced by XPO1 inhibitors provides preclinical evidence of selective activity of these drugs, justifying further clinical studies of these small molecules for the treatment ofTET2-mutant hematopoietic malignancies and to suppress clonal expansion in age-relatedTET2-mutant clonal hematopoiesis.

Anaplastic large cell lymphoma (ALCL) is an aggressive, CD30+ T-cell lymphoma of children and adults. ALK fusion transcripts or mutations in the JAK-STAT pathway are observed in most ALCL tumors, but the mechanisms underlying tumorigenesis are not fully understood. Here we show that dysregulated STAT3, together with a core transcriptional regulatory circuit consisting of BATF3–IRF4– IKZF1, co-occupies gene enhancers to establish an oncogenic transcription program and maintain the malignant state of ALCL. Critical downstream targets of this network in ALCL cells include the proto-oncogene MYC, which requires active STAT3 to facilitate high levels of MYC transcription. The activity of this auto-regulatory transcription loop is reinforced by MYC binding to the enhancer regions associated with STAT3 and each of the core regulatory transcription factors. These findings provide new insights for understanding how dysregulated signaling pathways hijack cell-type-specific transcriptional machinery to drive tumorigenesis and create therapeutic vulnerabilities in genetically defined tumors.

Description, Retinoic acid reprograms neuroblastoma cell identity by remodeling the core transcriptional regulatory circuitry., Neuroblastoma cell identity depends on a core regulatory circuit (CRC) of transcription factors that collaborate with MYCN to drive the oncogenic gene expression program. For neuroblastomas dependent on the adrenergic CRC, treatment with retinoids can inhibit cell growth and induce differentiation. Here, we show that when MYCN-amplified neuroblastoma cells are treated with retinoic acid, histone H3K27 acetylation and methylation become redistributed to decommission super-enhancers driving the expression of PHOX2B and GATA3, together with the activation of new super-enhancers that drive high levels of MEIS1 and SOX4 expression. These findings indicate that treatment with retinoids can reprogram the enhancer landscape, resulting in down-regulation of MYCN expression, while establishing a new retino-sympathetic CRC that causes proliferative arrest and sympathetic differentiation. Thus, we provide mechanisms that account for the beneficial effects of retinoids in high-risk neuroblastoma and explain the rapid down-regulation of expression of MYCN despite massive levels of amplification of this gene.