Influenced by the Wrong Crowd

Science's STKE  19 Jun 2007:
Vol. 2007, Issue 391, pp. tw214
DOI: 10.1126/stke.3912007tw214

Two studies by Walkley et al. investigated the role of intrinsic and extrinsic factors in regulating cell cycle and fate of hematopoietic stem cells (HSCs), which reside in specialized niches in the bone marrow and give rise to the cells of the hematopoietic system (see Perry and Li). Although most HSCs maintain a relatively quiescent state, they can be stimulated to enter the cell cycle when hematopoiesis is required. The retinoblastoma (RB) tumor suppressor plays a critical role in cell cycle regulation and, in the first study, Walkley et al. examined the effects of Rb deletion on hematopoiesis. Widespread loss of RB throughout the mouse hematopoietic system led to profound myeloproliferation, characterized by an increase in the numbers of circulating progenitor cells and extramedullary hematopoiesis. There was a loss of trabecular bone (a HSC niche) and HSCs from the bone marrow, and eventual hematopoietic failure. When RB loss was restricted to cells of the myeloid lineage (granulocytes, macrophages, and osteoclasts), however, myeloproliferation did not occur. Transplantation indicated that loss of RB from hematopoietic niche alone was also not sufficient to elicit myeloproliferation. Rather, it depended on RB loss from both the bone marrow microenvironment and cells of myeloid lineage. In the second study, Walkley et al. showed that mice lacking the retinoic acid receptor γ (RARγ) also developed a myeloproliferative condition, with increased numbers of granulocytes in the bone marrow, peripheral blood, and spleen. Again, there was a loss of trabecular bone and excessive extramedullary hematopoiesis. In mice lacking RARγ, however, transplantation analysis indicated that myeloproliferation depended only on an abnormal bone marrow microenvironment. Loss of the RARγ was associated with an increase in tumor necrosis factor α (TNF-α) in bone marrow, thymus, and spleen; moreover, the hematological abnormalities were partially rescued in mice transplanted with hematopoietic cells lacking TNF-α. Both studies underline the importance of the bone marrow microenvironment to normal hematopoiesis and the contribution of an aberrant niche to myeloproliferative disease.

C. R. Walkley, J. M. Shea, N. A. Sims, L. E. Purton, S. H. Orkin, Rb regulates interactions between hematopoietic stem cells and their bone marrow microenvironment. Cell 129, 1081-1095 (2007). [PubMed]

C. R. Walkley, G. Haines Olsen, S. Dworkin, S. A. Fabb, J. Swann, G. A. McArthur, S. V. Westmoreland, P. Chambon, D. T. Scadden, L. E. Purton, A microenvironment-induced myeloproliferative syndrome caused by retinoic acid receptor γ deficiency. Cell 129, 1097-1110 (2007). [PubMed]

J. M. Perry, L. Li, Disrupting the stem cell niche: Good seeds in bad soil. Cell 129,1045-1047 (2007). [PubMed]