Deregulated mitochondrial metabolism is associated with a variety of hematopoietic disorders, including hematological malignancies. However, it remains poorly defined how mitochondrial metabolism coordinates hematopoietic cell development. Lack of such knowledge impedes understanding of and development of therapeutics for these diseases. In the previous funding period we demonstrated that PTPMT1, a Pten-like mitochondrial phosphatidylinositol phosphate phosphatase, plays a unique and crucial role in hematopoietic stem cells (HSCs). Deletion of PTPMT1 resulted in hematopoietic failure due to changes in the cell cycle and a complete block in the differentiation of HSCs. Strikingly, the absolute number of HSCs was increased by ~25-fold in the knockout mice. Moreover, although depletion of PTPMT1 from the entire hematopoietic system (including HSCs) caused hematopoietic failure and postnatal lethality, myeloid, T lymphoid, or B lymphoid lineage-specific knockout mice did not show any phenotypes, strongly suggesting that PTPMT1 is specifically important for stem cells, but not differentiated lineage progenitors. Mitochondrial aerobic metabolism of PTPMT1-depleted stem/progenitor (LSK) cells and lineage progenitors was decreased while cytosolic glycolysis was enhanced. Nevertheless, the detailed cellular and molecular mechanisms by which PTPMT1 deficiency alters cellular metabolism and profoundly deregulates stem cell activities remain to be determined. The objective of this renewal application is to further understand the metabolic regulation of HSCs by defining the role and acting mechanisms of PTPMT1. The central hypothesis is that PTPMT1 coordinates HSC activities (self-renewal, differentiation, and transformation) by controlling the balance between mitochondrial metabolism and cytosolic glycolysis. This hypothesis has been formulated on the basis of our work in the last funding cycle and recent preliminary studies. We plan to test our hypothesis and accomplish the objectives of this proposal by pursuing the following three aims. 1). To define the cellular mechanisms of the crucial role of PTPMT1 in hematopoiesis. 2). To determine the molecular mechanisms by which PTPMT1 deficiency reprograms cellular metabolism. 3). To investigate the role of PTPMT1 in leukemic transformation of stem cells and progenitors. The studies proposed in this application will greatly advance our understanding of how coordinated mitochondrial metabolism/bioenergetics, glycolysis, and glutaminolysis orchestrate HSC biology. These data will contribute to a much deeper understanding of the pathophysiology of blood disorders associated with deregulated mitochondrial function, which will help identify molecular targets for novel therapeutic interventions for these diseases.
Deregulated mitochondrial metabolism is associated with a variety of hematopoietic disorders, including hematological malignancies. However, it remains poorly defined how mitochondrial metabolism coordinates hematopoietic cell development. The project proposed in this application seeks to address this problem by determining the role and metabolic mechanisms of the mitochondrial phosphatase PTPMT1 in hematopoietic stem cells. This study will contribute to a greater understanding of the pathophysiology of blood disorders associated with deregulated mitochondrial function, which will help identify molecular targets for novel therapeutic interventions for these diseases.
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|Liu, W; Yu, W-M; Zhang, J et al. (2017) Inhibition of the Gab2/PI3K/mTOR signaling ameliorates myeloid malignancy caused by Ptpn11 (Shp2) gain-of-function mutations. Leukemia 31:1415-1422|
|Dong, Lei; Zheng, Hong; Qu, Cheng-Kui (2017) CCL3 is a key mediator for the leukemogenic effect of Ptpn11-activating mutations in the stem-cell microenvironment. Blood 130:1471-1474|
|Ni, Fang; Qu, Cheng-Kui (2016) A metabolic stress-induced cell cycle checkpoint in stem cells. Cell Cycle 15:2539-2540|
|Dong, Lei; Yu, Wen-Mei; Zheng, Hong et al. (2016) Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment. Nature 539:304-308|
|Liu, Xia; Zheng, Hong; Li, Xiaobo et al. (2016) Gain-of-function mutations of Ptpn11 (Shp2) cause aberrant mitosis and increase susceptibility to DNA damage-induced malignancies. Proc Natl Acad Sci U S A 113:984-9|
|Liu, Xia; Zheng, Hong; Yu, Wen-Mei et al. (2015) Maintenance of mouse hematopoietic stem cells ex vivo by reprogramming cellular metabolism. Blood 125:1562-5|
|Dong, Lei; Qu, Cheng-Kui (2014) Flow cytometric analysis of signaling and apoptosis in hematopoietic stem cells. Methods Mol Biol 1185:79-87|
|Xu, Dan; Zheng, Hong; Yu, Wen-Mei et al. (2013) Activating mutations in protein tyrosine phosphatase Ptpn11 (Shp2) enhance reactive oxygen species production that contributes to myeloproliferative disorder. PLoS One 8:e63152|
|Yu, Wen-Mei; Liu, Xia; Shen, Jinhua et al. (2013) Metabolic regulation by the mitochondrial phosphatase PTPMT1 is required for hematopoietic stem cell differentiation. Cell Stem Cell 12:62-74|
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