Hematopoietic Stem Cell Quiescence Is Maintained by Compound Contributions of the Retinoblastoma Gene Family

Abstract

Individual members of the retinoblastoma (Rb) tumor suppressor gene family serve critical roles in the control of cellular proliferation and differentiation but the extent of their contributions is masked by redundant and compensatory mechanisms. Here, we employed a conditional knockout strategy to simultaneously inactivate all three members, Rb, p107, and p130, in adult hematopoietic stem cells (HSCs). Rb family triple knockout (TKO) mice develop a cell-intrinsic myeloproliferation that originates from hyperproliferative early hematopoietic progenitors and is accompanied by increased apoptosis in lymphoid progenitor populations. Loss of quiescence in the TKO HSC pool is associated with an expansion of these mutant stem cells, but also with an enhanced mobilization and an impaired reconstitution potential upon transplantation. The presence of a single p107 allele is sufficient to largely rescue these defects. Thus, Rb family members collectively maintain HSC quiescence and the balance between lymphoid and myeloid cell fates in the hematopoietic system.

Characterization of the cell of origin for small cell lung cancer

“…This model highlighting a role for RB and p53 in stem/progenitor cell populations is compatible with other mouse models of human cancers associated with loss of RB and p53 function, including in the blood compartment, in bones, in the retina and in the mammary epithelium. [35][36][37][38][39] However, the identity of potential neuroendocrine cell progenitors in adult lung tissue has not yet been established.…”

Cell cycle regulation in hematopoietic stem cells

“…The Ink4 family includes the CKIs p15 Ink4b , p16 Ink4a , p18 Ink4c , and p19 Ink4d , and a functionally distinct protein, p19 ARF that is encoded by an alternate reading frame within the Ink4a locus, which also encodes p16 Ink4a (Sherr 2001). The Ink4 adult mice resulted in a robust cell-intrinsic myeloproliferation phenotype leading to the death of the animals by 1-3 mo after gene inactivation (Viatour et al, 2008). This was accompanied by an increase in both HSC proliferation and absolute cell numbers, and by severe defects in HSC self-renewal as BM from mice deficient in all three Rb family genes had grossly impaired reconstitution after transplantation (Viatour et al, 2008).…”

“…The Ink4 adult mice resulted in a robust cell-intrinsic myeloproliferation phenotype leading to the death of the animals by 1-3 mo after gene inactivation (Viatour et al, 2008). This was accompanied by an increase in both HSC proliferation and absolute cell numbers, and by severe defects in HSC self-renewal as BM from mice deficient in all three Rb family genes had grossly impaired reconstitution after transplantation (Viatour et al, 2008). Taken together, these findings indicate that Rb family members play critical, albeit overlapping roles in the regulation of HSC quiescence and continued self-renewal activity.…”

The RB family is required for the self-renewal and survival of human embryonic stem cells

“…Thus, the RB pathway controls cellular processes that are critically linked to stem cell properties. Accordingly, RB and its two family members p107 and p130 are important regulators of adult stem cell and progenitor populations [10][11][12][13][14][15] .…”