A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia

Abstract

The molecular regulation of human hematopoietic stem cell (HSC) self-renewal is therapeutically important, but limitations in experimental systems and interspecies variation have constrained our knowledge of this process. Here, we have studied a rare genetic disorder due to MECOM haploinsufficiency, characterized by an early-onset absence of HSCs in vivo. By generating a faithful model of this disorder in primary human HSCs and coupling functional studies with integrative single-cell genomic analyses, we uncover a key transcriptional network involving hundreds of genes that is required for HSC self-renewal. Through our analyses, we nominate cooperating transcriptional regulators and identify how MECOM prevents the CTCF-dependent genome reorganization that occurs as HSCs exit quiescence. Strikingly, we show that this transcriptional network is co-opted in high-risk leukemias, thereby enabling these cancers to acquire stem cell properties. Collectively, we illuminate a regulatory network necessary for HSC self-renewal through the study of a rare experiment of nature.

Human hematopoietic stem cell vulnerability to ferroptosis

“…Concomitantly, we observed a reduction of both long term (LT-) and short term phenotypic HSCs (ST-HSCs) (Figure 1B, S1D). Given the imprecision of surface markers to confidently delineate molecularly-defined HSCs (Liggett and Sankaran, 2020; Voit et al, 2022), we performed single cell RNA sequencing (scRNA-seq) on AAVS1 control and MYSM1 edited CD34 + CD45RA - CD90 + cells and observed a significant reduction of cells harboring a molecular signature known to enrich for HSCs with MYSM1 editing (Bao et al, 2020) (Figure 1C-D).…”

“…To fully characterize the role of MYSM1 in human hematopoiesis, we transplanted AAVS1 control and MYSM1 edited cord blood CD34 + HSPCs into the NOD.Cg-Kit W-41J Tyr + Prkdc scid Il2rg tm1Wjl /ThomJ (NBSGW) strain of immunodeficient and Kit mutant mice (Fiorini et al, 2017; McIntosh et al, 2015; Voit et al, 2022). Consistent with the in vitro HSC depletion phenotype, there was significantly lower human CD45 + cell engraftment in the peripheral blood, bone marrow, and spleen at 4 months post-transplantation (Figure 1E, S1E), when hematopoiesis will predominantly be driven by transplanted HSCs.…”

Expanded phenotypic and hematologic abnormalities beyond bone marrow failure in MECOM‐associated syndromes

“…It remains possible that the patient's phenotype as presented in the manuscript, could partially be related to another gene in the deletion. The variable phenotypes observed in MECOM-associated syndrome may suggest additional modifiers that affect genetic expression either of MECOM itself or of its transcription network, which is critical for enabling effective hematopoietic stem cell self-renewal (Voit et al, 2021). A deeper understanding of the mechanisms through which these phenotypes vary and how they impact hematopoietic stem cell function will not only provide insights into this rare disorder but will more broadly inform our understanding of stem cell biology, which could also be valuable.…”