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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK050234-15A1
Application #
8239325
Study Section
Molecular and Cellular Hematology (MCH)
Program Officer
Wright, Daniel G
Project Start
1995-08-01
Project End
2013-08-31
Budget Start
2012-09-30
Budget End
2013-08-31
Support Year
15
Fiscal Year
2012
Total Cost
$199,084
Indirect Cost
$74,084
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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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