KIT Receptor Gain-of-Function in Hematopoiesis Enhances Stem Cell Self-Renewal and Promotes Progenitor Cell Expansion

Abstract

The KIT receptor tyrosine kinase has important roles in hematopoiesis. We have recently produced a mouse model for imatinib resistant gastrointestinal stromal tumor (GIST) carrying the Kit V558D and Kit T669I (human KIT T670I ) mutations found in imatinib-resistant GIST. The Kit V558D;T669I/1 mice developed microcytic erythrocytosis with an increase in erythroid progenitor numbers, a phenotype previously seen only in mouse models of polycythemia vera with alterations in Epo or Jak2. Significantly, the increased hematocrit observed in Kit V558D;T669I/1 mice normalized upon splenectomy. In accordance with increased erythroid progenitors, myeloerythroid progenitor numbers were also elevated in the Kit V558D;T669I/1 mice. Hematopoietic stem cell (HSC) numbers in the bone marrow (BM) of Kit V558D;T669I/1 mice were unchanged in comparison to wild-type mice. However, increased HSC numbers were observed in fetal livers and the spleen and peripheral blood of adult Kit V558D;T669I/1 mice. Importantly, HSC from Kit V558D;T669I/1 BM had a competitive advantage over wild-type HSC. In response to 5-fluorouracil treatment, elevated numbers of dividing Lin 2 Sca 1 cells were found in the Kit V558D;T669I/1 BM compared to wild type. Our study demonstrates that signaling from the Kit V558D;T669I/1 receptor has important consequences in hematopoiesis enhancing HSC self-renewal and resulting in increased erythropoiesis.

Hematopoietic Signaling Mechanism Revealed from a Stem/Progenitor Cell Cistrome

“…The RNA-seq analysis indicated that Samd14 knockdown decreased c-Kit expression in erythroid precursor cells (R1) (~1.4 fold, q = 0.04), and c-Kit promotes HSPC self-renewal (Deshpande et al, 2013). Transferrin receptor ( Tfrc ), Cd47 , Epo receptor ( Epor ) and Flt3 were unchanged (Figure 5A).…”

“…AKT activation can mediate c-Kit signaling (Blume-Jensen et al, 1998; Ma et al, 2012b) and SCF/c-Kit signaling stimulates HSPC self-renewal (Deshpande et al, 2013). GATA-1 repression and GATA-2 activation of Kit correlates with occupancy of an intron 1 and an upstream cis -element, respectively (Jing et al, 2008; Munugalavadla et al, 2005).…”

Dasatinib promotes the activation of quiescent hematopoietic stem cells in mice

“…Surprisingly however dasatinib did not affect the numbers of hematopoietic stem cells (HSC) or progenitors. This was unexpected given dasatinib's ability to inhibit c-Kit, and the in vivo requirement of these cells for c-Kit signaling [14][15][16]. We did however find that serum from dasatinib-dosed mice showed higher levels of stem cell factor (SCF), i.e.…”

Functional Analysis of KIT Gene Structural Mutations Causing the Porcine Dominant White Phenotype Using Genome Edited Mouse Models

“…In addition, we found that the number of white blood cells (WBCs) and lymphocytes (LYMs) was over twofold higher in KIT Dup/+ mice than that in WT mice ( Supplementary Table S3 and Figure S4). A previous study found that a gain-of-function KIT mutation promoted myeloid progenitor expansion, and lead to an increased number of WBCs (Deshpande et al, 2013). Therefore, unlike the situation in skin tissue, the KIT CDS duplication may have a stronger effect on PI3K and MAPK signaling in the hematological system, thus leading to an increase in the number of WBCs.…”