AML1/Runx1 Negatively Regulates Quiescent Hematopoietic Stem Cells in Adult Hematopoiesis

Abstract

Transcription factor AML1/Runx1, initially isolated from the t(8;21) chromosomal translocation in human leukemia, is essential for the development of multilineage hematopoiesis in mouse embryos. AML1 negatively regulates the number of immature hematopoietic cells in adult hematopoiesis, whereas it is required for megakaryocytic maturation and lymphocytic development. However, it remains yet to be determined how AML1 contributes to homeostasis of hematopoietic stem cells (HSCs). To address this issue, we analyzed in detail HSC function in the absence of AML1. Notably, cells in the Hoechst 33342 side population fraction are increased in number in AML1-deficient bone marrow, which suggests enrichment of quiescent HSCs. We also found an increase in HSC number within the AML1-deficient bone marrow using limiting dilution bone marrow transplantation assays. These results indicate that the number of quiescent HSCs is negatively regulated by AML1.

Novel function of PITH domain-containing 1 as an activator of internal ribosomal entry site to enhance RUNX1 expression and promote megakaryocyte differentiation

“…It is also essential for terminal differentiation of megakaryocytes at the polyploidization stage and for the maturation of T and B lymphocytes [5,6]. Furthermore, RUNX1 negatively regulates the proliferation of HSCs and myeloid progenitors [7,8]. In leukemia, the mutant RUXN1 or chimeric gene product repressed the function of remaining endogenous RUNX1 in hematopoiesis [4], suggesting that the expansion of hematopoietic stem and progenitor cells due to RUNX1-deficiency or dysfunction may be an important cause of human leukemias.…”

“…P2 drives transcription of RUNX1a/b and multiple ATG in 5 0 UTR impairs capdependent translation of RUNX1a/b. Instead, P2-UTR contains an internal ribosome entry site (IRES) element that is critical for translation of RUNX1a/b [7]. P1-UTRdependent RUNX1 expression is not required for embryonic survival but affects hematopoietic development while P2-UTR-dependent RUNX1 expression is critical for definitive hematopoiesis, leukemogenesis, angiogenesis, thymic development, and postnatal survival [10].…”

Polycomb group ring finger 1 cooperates with Runx1 in regulating differentiation and self-renewal of hematopoietic cells

“…[2][3][4] Conditional Runx1-knockout mice display an increased pool of hematopoietic stem cells (HSCs), myeloid progenitor cells (MPCs), and granulocyte-macrophage progenitors (GMPs) in the BM, demonstrating a role of Runx1 in the maturation of these cells. [2][3][4] In addition to its effect on immature hematopoietic cells, Runx1 is required for efficient differentiation of both the myeloid and lymphoid lineage during later steps of hematopoiesis. Conditional Runx1-knockout mice show a megakaryocyte maturation arrest leading to micromegakaryocytes in the BM and thrombocytopenia in the blood.…”

The RUNX1–PU.1 axis in the control of hematopoiesis

“…These studies overall show that loss of RUNX1 in adult stages does not totally compromise hematopoiesis in general (i.e., HSCs are still present) [28][29][30], but causes expansion of a lineage negative Sca1 + Kit + (LSK) population and the myeloid progenitor compartment in bone marrow [30,31]. Moreover, in vivo long-term HSC activity is negatively regulated by RUNX1 [32].…”