This proposal focuses on defining how energy regulation alters normal and malignant hematopoietic stem/progenitor (HSPC) function. Our preliminary data indicate that there are specific enzyme regulators of cell metabolism that selectively and differentially affect normal and malignant HSPC. The studies to date have included focused manipulation of pyruvate kinase isoforms (PK-M1 and -M2) implicated in the Warburg effect of solid tumors using engineered mouse models. These studies indicate that normal HSPC are advantaged in competitive repopulation experiments in the absence of PK-M2. In striking and potentially therapeutically useful distinction, leukemogenesis with Bcr-Abl is markedly inhibited in the absence of PK-M2. These studies are the basis for a more detailed understanding of the metabolic parameters governing the phenotypic changes and examination of whether the distinctions are leukemogeneic allele-specific. Based on the findings above, we also embarked on a forward shRNA screen to evaluate other metabolic enzymes and their differential effects on normal and malignant HSPC. Seven additional candidates were identified, including at least one thought to be downstream of the PK-M2 isoform. Studying the impact of these enzymes alone and in conjunction with PK-M2 to assess potential epistasis is proposed as a means to define new and potentially additive metabolic vulnerabilities of the leukemic cell that may spare normal HSPC function. These studies offer the potential for both new understanding of the metabolic governance of stem cells and new targets to influence the competitive relationship of normal and leukemic cells to the advantage of the normal cells.
Cellular energetics controlling normal and malignant hematopoietic stem/progenitor cells are distinctive and point to novel means of intervening to competitively advantage normal cells. Using genetic tools in mouse models, we propose defining in-depth unique metabolic vulnerabilities of leukemic cells.
|Wang, Ying-Hua; Israelsen, William J; Lee, Dongjun et al. (2014) Cell-state-specific metabolic dependency in hematopoiesis and leukemogenesis. Cell 158:1309-23|
|Kharchenko, Peter V; Silberstein, Lev; Scadden, David T (2014) Bayesian approach to single-cell differential expression analysis. Nat Methods 11:740-2|
|Scadden, David T (2014) Nice neighborhood: emerging concepts of the stem cell niche. Cell 157:41-50|
|Sykes, Stephen M; Scadden, David T (2013) Modeling human hematopoietic stem cell biology in the mouse. Semin Hematol 50:92-100|
|Ferraro, Francesca; Lymperi, Stefania; Mendez-Ferrer, Simon et al. (2011) Diabetes impairs hematopoietic stem cell mobilization by altering niche function. Sci Transl Med 3:104ra101|
|Sykes, Stephen M; Lane, Steven W; Bullinger, Lars et al. (2011) AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias. Cell 146:697-708|
|Vunjak-Novakovic, Gordana; Scadden, David T (2011) Biomimetic platforms for human stem cell research. Cell Stem Cell 8:252-61|
|Gurumurthy, Sushma; Xie, Stephanie Z; Alagesan, Brinda et al. (2010) The Lkb1 metabolic sensor maintains haematopoietic stem cell survival. Nature 468:659-63|
|Mukherjee, Siddhartha; Raje, Noopur; Schoonmaker, Jesse A et al. (2008) Pharmacologic targeting of a stem/progenitor population in vivo is associated with enhanced bone regeneration in mice. J Clin Invest 118:491-504|
|Fleming, Heather E; Janzen, Viktor; Lo Celso, Cristina et al. (2008) Wnt signaling in the niche enforces hematopoietic stem cell quiescence and is necessary to preserve self-renewal in vivo. Cell Stem Cell 2:274-83|
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