Abstract SY13-04: Stem cell self-renewal and cancer

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Abstract Haematopoietic stem cell self-renewal and leukemogenesis “Pre-leukemic” mutations are thought to promote clonal expansion of haematopoietic stem cells (HSCs) by increasing self-renewal and competitiveness; however, mutations that increase HSC proliferation tend to reduce competitiveness and self-renewal potential, raising the question of how a mutant HSC can sustainably outcompete wild-type HSCs. Activating mutations in NRAS are prevalent in human myeloproliferative neoplasms and leukemia. We found that a single allele of oncogenic NrasG12D increases HSC proliferation but also increases reconstituting and self-renewal potential upon serial transplantation in irradiated mice, all prior to leukemia initiation. NrasG12D also confers long-term self-renewal potential upon multipotent progenitors. To explore the mechanism by which NrasG12D promotes HSC proliferation and self-renewal we assessed cell cycle kinetics using H2B-GFP label retention and BrdU incorporation. NrasG12D had a bimodal effect on HSCs, increasing the rate at which some HSCs divide and reducing the rate at which others divide. This mirrored bimodal effects on reconstituting potential as rarely dividing NrasG12D HSCs outcompeted wild-type HSCs while frequently dividing NrasG12D HSCs did not. NrasG12D had these effects by promoting STAT5 signaling, inducing different transcriptional responses in different subsets of HSCs. One signal can therefore increase HSC proliferation, competitiveness, and self-renewal through bimodal effects on HSC gene expression, cycling, and reconstituting potential. We have also developed methods for studying protein synthesis by individual stem cells in vivo. Currently, there are almost no data on protein synthesis in any somatic stem cell. We found that the amount of protein synthesized per hour in HSCs in vivo was lower than in most other haematopoietic cells, even if we controlled for differences in cell cycle status or forced HSCs to undergo self-renewing divisions. Reduced ribosomal function in Rpl24Bst/+ mice further reduced protein synthesis in HSCs and impaired HSC function. Pten deletion increased protein synthesis in HSCs but also reduced HSC function. Rpl24Bst/+ cell-autonomously rescued the effects of Pten deletion in HSCs, blocking the increase in protein synthesis, restoring HSC function, and delaying leukemogenesis. Pten deficiency thus depletes HSCs and promotes leukemia partly by increasing protein synthesis. Increased or decreased protein synthesis impairs HSC function. Citation Format: Sean J. Morrison. Stem cell self-renewal and cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY13-04. doi:10.1158/1538-7445.AM2014-SY13-04