Runx3 deficiency results in myeloproliferative disorder in aged mice

Abstract

Key Points Runx3 conditional knockout mice develop a myeloproliferative disorder when aged. Runx3-deficient cells show hypersensitivity to G-CSF.

The Runx-PU.1 pathway preserves normal and AML/ETO9a leukemic stem cells

“…[21][22][23][24] Here we show that Runx1 deletion led to Runx3 upregulation in HSCs. Our data together with data from a recent study demonstrating a functional role of Runx3 in HSCs 25 suggests that Runx3 partially substitutes for Runx1 function. The functional redundancy of Runx factors was further supported by a report showing Runx2 upregulation in MLL-AF9 leukemia.…”

“…Indeed, it was shown recently that Runx3 has an antiproliferative function in HSCs and/or progenitors of aged mice. 25 In this report, using a knockin mouse model in which binding of all Runx factors at the 214kb upstream enhancer of PU.1 is abolished, 11 we could rule out any compensatory effects of individual Runx family members. By using this model, we observed major importance of the Runx-PU.1 pathway for HSC function.…”

Early Life Lead Exposure Causes Gender-Specific Changes in the DNA Methylation Profile of DNA Extracted from Dried Blood Spots

“…We saw a Pb-dependent increase in DNA methylation for another member of Runt domain associated transcription factor, RUNX3 (Table 2 & Supplementary Figure 1B) only in females. RUNX3 deficiency is shown to be associated with myeloproliferative disorder in mouse [59]. Wolff et al reported that the DNA methylation of RUNX3 increases with age and the process is further accelerated by smoking [60].…”

Runx1 and Cbfβ regulate the development of Flt3+ dendritic cell progenitors and restrict myeloproliferative disorder

“…Alteration of Runx1 or Cbfb function caused by chromosomal translocations is frequently found in human acute myelogenous leukemia (AML), 10 whereas Runx3 deficiency has been implicated in myeloproliferative diseases (MPDs) in aged mice. 11 Although Runx1 is essential for HSC formation from hemogenic endothelial cells during embryogenesis, conditional deletion of Runx1 in HSCs neither influences the survival of mice nor the maintenance of long-term HSCs. 12,13 By contrast, Runx1 is required for the development of B and T lymphocytes and megakaryocytes, [14][15][16][17] suggesting that it functions in cell fate decisions during BM progenitor differentiation.…”