Rac GTPase inhibition in Chronic Myelogenous Leukemia. Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disease with deregulated expression of the fusion gene p210-BCR-ABL. P210-BCR-ABL is needed to initiate and maintain CML. Molecular targeting of p210-BCR-ABL by inhibiting the abl kinase activity can suppress growth and induces apoptosis of CML cells. However, Abl kinase inhibitors are not able to eradicate the disease and alternatives targeting signaling downstream of p210-BCR-ABL in HSC/P are required. Since dysregulated Rac activity has been implicated in cancer transformation (and we have previously shown the role of Rac1 and Rac2 Rho GTPases in regulating proliferation, stem cell localization and apoptosis of HSC/P), we hypothesize that full p210-BCR-ABL mediated transformation of hematopoietic stem cells requires Rac activity and that Rac GTPase isoforms play distinct roles in the initiation and/or maintenance of p210-BCR- ABL-induced leukemia. By taking advantage of gene-targeted mice lacking Rac1, Rac2 and Rac3 and a pharmacological approach in vitro and in vivo in murine and human disease, we have generated preliminary data to indicate that Rac proteins play an essential role in the leukemogenic effects of p210-BCR-ABL in vitro and in vivo.
In Specific Aim 1, we will investigate the requirement of the Rho GTPases Rac1, Rac2 and Rac3, or combinations in vitro and in vivo in leukemia initiation and in cell transformation. We will also investigate the role of Rac effectors and downstream signals in leukemia initiation.
In Specific Aim 2, we will analyze whether Rac (and specific Rac isoforms) play distinct or redundant roles in the maintenance of leukeminas induced by p210-BCR-ABL. Finally, we will analyze whether the downstream signals activated by Rac for leukemic maintenance are different from the ones required for initiation. The results obtained from this project will validate the potential role of Rac GTPases as novel molecular targets for CML and dissect out the signals induced by Rac activation required for leukemogenesis and potential new targets for leukemic therapy.

Public Health Relevance

Chronic myelogenous leukemia is a disease caused by the expression of an abnormal protein called BCR/ABL. Rac GTPases are a group of proteins that act as molecular switches in the cells. We will analyze whether Rac GTPases are critical for the development of leukemias induced by BCR/ABL and analyze the specific mechanisms depending on Rac GTPases responsible for leukemia formation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL087159-04
Application #
8235866
Study Section
Hematopoiesis Study Section (HP)
Program Officer
Di Fronzo, Nancy L
Project Start
2009-04-06
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
4
Fiscal Year
2012
Total Cost
$371,250
Indirect Cost
$123,750
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Chang, Kyung Hee; Nayak, Ramesh C; Roy, Swarnava et al. (2015) Vasculopathy-associated hyperangiotensinemia mobilizes haematopoietic stem cells/progenitors through endothelial ATâ‚‚R and cytoskeletal dysregulation. Nat Commun 6:5914
Chang, Kyung Hee; Sengupta, Amitava; Nayak, Ramesh C et al. (2014) p62 is required for stem cell/progenitor retention through inhibition of IKK/NF-κB/Ccl4 signaling at the bone marrow macrophage-osteoblast niche. Cell Rep 9:2084-97
Nayak, Ramesh C; Chang, Kyung-Hee; Vaitinadin, Nataraja-Sarma et al. (2013) Rho GTPases control specific cytoskeleton-dependent functions of hematopoietic stem cells. Immunol Rev 256:255-68
Taniguchi Ishikawa, E; Chang, K H; Nayak, R et al. (2013) Klf5 controls bone marrow homing of stem cells and progenitors through Rab5-mediated β1/β2-integrin trafficking. Nat Commun 4:1660
Sengupta, Amitava; Ficker, Ashley M; Dunn, Susan K et al. (2012) Bmi1 reprograms CML B-lymphoid progenitors to become B-ALL-initiating cells. Blood 119:494-502
Taniguchi Ishikawa, Eri; Gonzalez-Nieto, Daniel; Ghiaur, Gabriel et al. (2012) Connexin-43 prevents hematopoietic stem cell senescence through transfer of reactive oxygen species to bone marrow stromal cells. Proc Natl Acad Sci U S A 109:9071-6
Gonzalez-Nieto, Daniel; Li, Lina; Kohler, Anja et al. (2012) Connexin-43 in the osteogenic BM niche regulates its cellular composition and the bidirectional traffic of hematopoietic stem cells and progenitors. Blood 119:5144-54
Chang, Kyung Hee; Sanchez-Aguilera, Abel; Shen, Shuhong et al. (2012) Vav3 collaborates with p190-BCR-ABL in lymphoid progenitor leukemogenesis, proliferation, and survival. Blood 120:800-11
Cancelas, J A (2011) On how Rac controls hematopoietic stem cell activity. Transfusion 51 Suppl 4:153S-159S
Sengupta, Amitava; Cancelas, Jose A (2011) A conundrum in mammalian hematopoietic stem cell polarity. Cell Cycle 10:4191-2

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