The cis-Regulatory DERARE Element Regulates Leukemogenesis

The HOX genes regulate hematopoietic stem cells (HSC) and can contribute to leukemogenesis, but the cis-regulatory elements responsible for maintaining HSC homeostasis remain largely unknown. Qian and colleagues found that Hoxb cluster genes (including Hoxb2, Hoxb5, and Hoxb6) and retinoic acid (RA) signaling genes were enriched in long-term HSCs, suggesting potential regulatory roles. Whole-genome bisulfite sequencing in HSPCs identified a highly conserved differentially methylated region in the Hoxb cluster, an RA-dependent cis-regulatory element termed distal element RARE (DERARE). Deletion of DERARE reduced the expression of Hoxb genes, indicating that it coordinates Hoxb cluster expression in HSCs. Further, DERARE deletion resulted in HSC defects, impairing their self-renewal and reconstitution capacities. RNA sequencing demonstrated the DERARE deletion–mediated downregulation of Hoxb genes resulted in reduced expression of downstream genes in the noncanonical WNT pathway, a key pathway in HSC homeostasis. Mechanistically, DNMT catalyzed DNA methylation of DERARE, which resulted in repression of Hoxb cluster expression. DNMT3A mutations occur frequently in patients with acute myeloid leukemia, and, accordingly, patients with AML had increased expression of HOXB genes. Moreover, reduced DERARE methylation was associated with DNMT3A mutations and with poorer survival in patients with AML. In vivo, mice engrafted with hypermethylated DERARE AML cells exhibited reduced leukemogenesis compared with hypomethylated DERARE due to DNMT3 mutation. Collectively, these findings elucidate a role for DERARE in maintaining normal hematopoiesis and suppressing leukemogenesis via HOXB cluster regulation and suggest that targeted DERARE methylation might improve survival in DNMT3A-mutant AML.

Qian P, De Kumar B, He XC, Nolte C, Gogol M, Ahn Y, et al. Retinoid-sensitive epigenetic regulation of the Hoxb cluster maintains normal hematopoiesis and inhibits leukemogenesis. Cell Stem Cell 2018;22:740–54.e7.

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