ABSTRACT
Therapy-related myeloid neoplasms (t-MNs) are high-risk late effects with poorly understood pathogenesis in cancer survivors. It has been postulated that, in some cases, hematopoietic stem and progenitor cells (HSPCs) harboring mutations are selected for by cytotoxic exposures and transform. Here, we evaluate this model in the context of deficiency of CUX1, a transcription factor encoded on chromosome 7q and deleted in half of t-MN cases. We report that CUX1 has a critical early role in the DNA repair process in HSPCs. Mechanistically, CUX1 recruits the histone methyltransferase EHMT2 to DNA breaks to promote downstream H3K9 and H3K27 methylation, phosphorylated ATM retention, subsequent γH2AX focus formation and propagation, and, ultimately, 53BP1 recruitment. Despite significant unrepaired DNA damage sustained in CUX1-deficient murine HSPCs after cytotoxic exposures, they continue to proliferate and expand, mimicking clonal hematopoiesis in patients postchemotherapy. As a consequence, preexisting CUX1 deficiency predisposes mice to highly penetrant and rapidly fatal therapy-related erythroleukemias. These findings establish the importance of epigenetic regulation of HSPC DNA repair and position CUX1 as a gatekeeper in myeloid transformation.
Subject(s)
Chromosomes, Mammalian , DNA Repair , Epigenesis, Genetic , Gene Expression Regulation, Leukemic , Homeodomain Proteins , Leukemia, Erythroblastic, Acute , Neoplasm Proteins , Neoplasms, Second Primary , Nuclear Proteins , Repressor Proteins , Animals , Chromosomes, Mammalian/genetics , Chromosomes, Mammalian/metabolism , Clonal Hematopoiesis , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Leukemia, Erythroblastic, Acute/genetics , Leukemia, Erythroblastic, Acute/metabolism , Mice , Mice, Transgenic , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Neoplasms, Second Primary/genetics , Neoplasms, Second Primary/metabolism , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Repressor Proteins/genetics , Repressor Proteins/metabolismABSTRACT
Many transcription factors (TFs) function as tumor suppressor genes with heterozygous phenotypes, yet haploinsufficiency generally has an underappreciated role in neoplasia. This is no less true in myeloid cells, which are normally regulated by a delicately balanced and interconnected transcriptional network. Detailed understanding of TF dose in this circuitry sheds light on the leukemic transcriptome. In this review, we discuss the emerging features of haploinsufficient transcription factors (HITFs). We posit that: (a) monoallelic and biallelic losses can have distinct cellular outcomes; (b) the activity of a TF exists in a greater range than the traditional Mendelian genetic doses; and (c) how a TF is deleted or mutated impacts the cellular phenotype. The net effect of a HITF is a myeloid differentiation block and increased intercellular heterogeneity in the course of myeloid neoplasia.