Abstract
RUNX1 encodes a DNA binding subunit of the core-binding transcription factors and is frequently mutated in acute leukemia, therapy-related leukemia, myelodysplastic syndrome, and chronic myelomonocytic leukemia. Mutations in RUNX1 are thought to confer upon hematopoietic stem cells (HSCs) a pre-leukemic state, but the fundamental properties of Runx1 deficient pre-leukemic HSCs are not well defined. Here we show that Runx1 deficiency decreases both apoptosis and proliferation, but only minimally impacts the frequency of long term repopulating HSCs (LT-HSCs). It has been variously reported that Runx1 loss increases LT-HSC numbers, decreases LT-HSC numbers, or causes age-related HSC exhaustion. We attempt to resolve these discrepancies by showing that Runx1 deficiency alters the expression of several key HSC markers, and that the number of functional LT-HSCs varies depending on the criteria used to score them. Finally, we identify genes and pathways, including the cell cycle and p53 pathways that are dysregulated in Runx1 deficient HSCs.
Highlights
One of the most commonly mutated genes in leukemia is RUNX1, which encodes a DNA-binding subunit of the heterodimeric core-binding factors
This expansion involved both lineage negative Sca1+ c-Kit+ (LSK) Flt3cells (LSKF-), which include all long term and short term repopulating hematopoietic stem cells (HSCs) (LT-HSCs and ST-HSCs), and LSKF+ cells which consist of early multipotent progenitors (MPPs) and lymphoid-primed MPPs (LMPPs) (Figure 1B,D) [24,25]
We examined the cell-intrinsic properties of Runx1 deficient HSCs using both phenotypic and functional assays
Summary
One of the most commonly mutated genes in leukemia is RUNX1, which encodes a DNA-binding subunit of the heterodimeric core-binding factors. Chromosomal translocations involving RUNX1 are found in multiple hematopoietic malignancies including acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), and therapy-related AML and myelodysplastic syndrome (MDS). Mono- or biallelic deletions, missense, nonsense, and frameshift mutations in RUNX1 are found in patients with de novo AML, MDS, chronic myelomonocytic leukemia, and in therapy-related MDS and AML [1,2,3,4,5,6,7]. A recent analysis of 449 de novo AML patients with normal karyotype or non complex chromosomal imbalances identified RUNX1 mutations in 32.7% of cases, including 65% of the least differentiated French-American-British (FAB) subtype (AML M0) [6]. The mechanism by which Runx loss contributes to AML or MDS is not entirely clear, nor is it understood why de novo AML associated with biallelic loss of function RUNX1 mutations confers a considerably worse prognosis than, for example, de novo AML with the (8;21) translocation [6,8,9]
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