Stem Cell c-KITandHOXB4Genes: Critical Roles and Mechanisms in Self-Renewal, Proliferation, and Differentiation

Abstract

Hematopoietic stem cells (HSCs) possess a distinct ability to perpetuate through self-renewal and to generate progeny that differentiate into mature cells of myeloid and lymphoid lineages. A better understanding of the molecular mechanisms by which HSCs replicate and differentiate from the perspective of developing new approaches for HSC transplantation is necessary for further advances. The interaction of the receptor tyrosine kinase--c-KIT--with its ligand stem cell factor plays a key role in HSC survival, mitogenesis, proliferation, differentiation, adhesion, homing, migration, and functional activation. Evidence that activating site-directed point mutations in the c-KIT gene contributes to its ligand-independent constitutive activation, which induces enhanced proliferation of HSCs, is accumulating. Similarly, and equally important, self-renewal is a process by which HSCs generate daughter cells via division. Self-renewal is necessary for retaining the HSC pool. Therefore, elucidating the molecular machinery that governs self-renewal is of key importance. The transcription factor, HOXB4 is a key molecule that has been reported to induce the in vitro expansion of HSCs via self-renewal. However, critical downstream effector molecules of HOXB4 remain to be determined. This concisely reviewed information on c-KIT and HOXB4 helps us to update our understanding of their function and mechanism of action in self-renewal, proliferation, and differentiation of HSCs, particularly modulation by c-KIT mutant interactions, and HOXB4 overexpression showing certain therapeutic implications.

Essential Role of Sox2 for the Establishment and Maintenance of the Germ Cell Line

“…Kit is subjected to tight transcriptional control, because it is essential not only for germ cells but also for hematopoietic stem cell and melanocyte development. Indeed, a variety of transcription factors are known to regulate Kit expression in hematopoiesis and melanogenesis [45], but the mechanisms that modulate Kit expression in the germline are probably multiple. While postnatally Sohlh1 and Sohlh2, two bHLH transcription factors, are essential for Kit expression in spermatogonia and possibly in oocytes, they are not required during PGCs differentiation [46].…”

Leukemic Cells Create Bone Marrow Niches That Disrupt the Behavior of Normal Hematopoietic Progenitor Cells

“…factor (SCF), an HPC growth factor and chemoattractant believed to play a role in HSC localization to endosteal niches (19)(20)(21)(22). SCF is produced by a wide variety of solid tumors (23)(24)(25)(26).…”

SOHLH1 and SOHLH2 control Kit expression during postnatal male germ cell development.

“…Indeed, a variety of transcription factors are known to regulate Kit expression in hematopoiesis and melanogenesis (reviewed by Sharma et al, 2006), but very little is known about the mechanisms that modulate Kit expression in the germline. In fetal oocytes, Kit is downregulated after meiotic entry, and is then upregulated perinatally to control oocyte growth.…”