RAC GTPASE INHIBITION IN CHRONIC MYELOGENOUS LEUKEMIA
Jose A Cancelas, Associate Professor
Children´s Hospital Med Ctr (cincinnati), 3333 Burnet Ave, Cincinnati, Oh 45229-3039
Grant 5R01HL087159-02 from National Heart, Lung, And Blood Institute
Abstract: 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. 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
Keywords: AKT; Acute leukemia; Adhesions; Akt protein; Apoptosis; Apoptosis Pathway; BCR-ABL; BCR-ABL Oncoprotein; BCR-ABL Protein Tyrosine Kinase; BCR/ABL; Biochemical; Blood (Leukemia); Blood Precursor Cell; CD34; CD34 gene; Cancers; Cell Communication and Signaling; Cell Cycle Progression; Cell Death, Programmed; Cell Function; Cell Process; Cell Signaling; Cell Survival; Cell Viability; Cell physiology; Cells; Cellular Function; Cellular Physiology; Cellular Process; Cellular Transformation; Cessation of life; Chronic Myeloid Leukemia; Chronic Phase CML; Chronic Phase Chronic Granulocytic Leukemia; Chronic Phase Chronic Myelocytic Leukemia; Data; Death; Development; Disease; Disorder; EC 2.7; Event; Fusion Proteins, bcr-abl; GTP Phosphohydrolases; GTPases; Gene Targeting; Generalized Growth; Granulocytic Leukemia, Chronic, Stable-Phase; Growth; Guanosine; Guanosine Triphosphate Phosphohydrolases; Guanosinetriphosphatases; HPCA1; Hematopoietic stem cells; Homing; In Vitro; Individual; Inositide Phospholipids; Inositol Phosphoglycerides; Inositol Phospholipids; Intracellular Communication and Signaling; Isoforms; Kinases; Leukemia, Granulocytic, Chronic; Leukemia, Granulocytic, Chronic-Phase; Leukemia, Myelogenous, Chronic-Phase; Leukemia, Myeloid, Chronic-Phase; Leukemia, Myeloid, Stable-Phase; Leukemias, General; Leukemic Hematopoietic Stem Cell; Leukemogenesis/Lymphomagenesis; Maintenance; Maintenances; Malignant Neoplasms; Malignant Tumor; Mammals, Mice; Mediating; Mice; Modeling; Molecular; Molecular Target; Mother Cells; Murine; Mus; Myelocytic Leukemia, Chronic; Myelogenous; Myelogenous Leukemia, Chronic; Myelogenous Leukemia, Chronic, Chronic-Phase; Myeloid; Myeloid Disease; Myeloid Leukemia, Chronic; Myeloid Leukemia, Chronic, Chronic-Phase; Myeloid Leukemia, Chronic, Stable-Phase; Myeloid Malignancy; Myeloid Neoplasm; Myeloid Tumor; Myeloproliferative Disorders; Myeloproliferative Tumors; Myeloproliferative disease; PKB protein; PTK Inhibitors; Pathway interactions; Patients; Ph 1 Chromosome; Ph1 Chromosome; Phenotype; Philadelphia Chromosome; Phosphatidyl Inositol; Phosphatidylinositols; Phosphoinositides; Phosphotransferases; Play; Progenitor Cells; Progenitor Cells, Hematopoietic; Protein Isoforms; Protein Kinase B; Protein Tyrosine Kinase Inhibitors; Proteins; Proto-Oncogene Proteins c-akt; PtdIns; RAC-PK protein; Role; STAT protein; Signal Pathway; Signal Transducer and Activator of Transcription; Signal Transduction; Signal Transduction Systems; Signaling; Stem cells; Subcellular Process; TC-25 GTP-Binding Protein; TK Inhibitors; Targetings, Gene; Tissue Growth; Transphosphorylases; Tyrosine Kinase Inhibitor; base; bcr-abl Fusion Proteins; biological signal transduction; c-akt protein; cell transformation; combinatorial; disease/disorder; dosage; fusion gene; gene product; guanosinetriphosphatase; human disease; in vivo; in vivo Model; kinase inhibitor; leukemia; leukemogenesis; malignancy; metaplastic cell transformation; migration; myeloproliferative neoplasm; neoplasm/cancer; new therapeutic target; novel; ontogeny; pathway; progenitor; protein-serine-threonine kinase (rac); proto-oncogene protein RAC; proto-oncogene protein akt; public health relevance; rac G Protein; rac GTP-Binding Proteins; rac Proteins; rac protein kinase; rac1 GTP-Binding Protein; rac1 Protein; ras-Related C3 Botulinum Toxin Substrate 1; related to A and C-protein; retroviral transduction; rho; rho G-Proteins; rho GTP-Binding Proteins; rho GTPases; rho Protein P21; rho Small GTP-Binding Proteins; small molecule; social role; transformed cells
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
Project start date: 2009-04-06
Project end date: 2013-02-28
Budget start date: 1-MAR-2010
Budget end date: 28-FEB-2011
PFA/PA: PA-07-070
5R01HL087159-02 (2010): $375000
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Jose A Cancelas
Rac GTPase Inhibition In Chronic Myelogenous Leukemia
Jose A Cancelas
Children´s Hospital Med Ctr (cincinnati)
Grant 1R01HL087159-01A2 from National Heart, Lung, And Blood Institute IRG: HP
Abstract: 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. 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
Project start date: 2009-04-06
Project end date: 2013-02-28
3R01HL087159-01A2S1 (2009): $213217