Document text
Principal Investigator: RAVI BHATIA
Organization: UNIVERSITY OF ALABAMA AT BIRMINGHAM
Fiscal Year: 2024
Award: $403,983
Funding agency: National Cancer Institute
PROJECT SUMMARY/ABSTRACT
Chronic myelogenous leukemia (CML) results from hematopoietic stem cell (HSC) transformation by the BCR-
ABL tyrosine kinase. Tyrosine kinase inhibitors (TKI) are effective in inducing remission and prolonging survival
in CML patients, but fail to eliminate primitive leukemia stem cells (LSC) that can regenerate disease. Most
patients need ongoing TKI treatment to maintain remission, and remain at risk of toxicity, financial hardship and
non-adherence. The long-term goal of our research is to improve understanding of mechanisms of LSC
resistance to treatment, to support development of effective and safe strategies for LSC targeting, and enhance
possibilities of treatment-free remissions in CML patients. Mitochondrial metabolism plays a critical regulatory
role in normal HSC function. CML LSC demonstrate increased mitochondrial oxidative phosphorylation
(OXPHOS) compared to low OXPHOS in normal HSC. However, mitochondria also play important roles in
metabolic processes besides OXPHOS, including fatty acid, glutamine and glucose oxidation, and generation of
biosynthetic intermediates. The rationale for our studies is that specific mitochondrial metabolic alterations that
contribute to altered LSC growth and TKI resistance are not known. Our preliminary studies show initial inhibition
of OXPHOS in CML LSC after TKI treatment, but subsequent restoration of OXPHOS, and increased fatty acid
oxidation (FAO), with continued treatment. A SIRT1, P53 and MYC regulatory network plays an important role
in LSC propagation. We show that SIRT1 and its target PGC-1α play an important role in increased OXPHOS in
CML LSC. PPARa, a PGC-1α-coactivated transcription factor and a key regulator of FAO, shows increased
expression in CML LSC after TKI treatment, and contributes to increased OXPHOS, proliferation and survival.
We will explore the hypothesis that increased FAO following BCR-ABL kinase inhibition, together with
maintenance of high levels of OXPHOS, glycolysis and glutaminolysis, contributes to TKI resistance in CML
LSC, and that metabolic regulatory mechanisms represent potential targets for elimination of TKI-treated CML
LSC. In Specific Aim 1 we will use a combination of gene expression, extracellular flux, metabolite profiling and
in vitro and in vivo metabolic labeling to study effects of TKI treatment on mitochondrial metabolism in CML LSC,
examine the role of SIRT1, PGC1a and PPARa in metabolic alterations, and study interactions of MYC and p53
regulatory networks with mitochondrial metabolism. In Specific Aim 2 we will investigate the role of increased
OXPHOS and FAO in promoting TKI resistance in CML LSC. Bone marrow microenvironment niches play a
critical role in maintaining quiescent, TKI-resistant LSC populations. However, the role of the microenvironment
in metabolic regulation of LSC growth is not known, and will be evaluated here . These studies are significant
since they are expected to identify mechanisms of metabolic regulation underlying TKI resistance in CML LSC,
establish connections between metabolism and other regulatory mechanisms in CML LSC, and identify new
targets for therapy. The concepts developed here will have broad implications for other malignancies.
Terms: <Active Oxygen><Antioncogene Protein p53><BCR-ABL Kinase><Basal Transcription Factor><Basal transcription factor genes><Bcr-Abl tyrosine kinase><Biology><Blood Precursor Cell><Bone Marrow><Bone Marrow Reticuloendothelial System><CXCL12><CXCL12 gene><CXCL12 protein><Cancers><Cell Communication and Signaling><Cell Death><Cell Function><Cell Growth and Maintenance><Cell Maintenance><Cell Physiology><Cell Process><Cell Signaling><Cell Survival><Cell Viability><Cellular Function><Cellular Metabolic Process><Cellular Physiology><Cellular Process><Cellular Tumor Antigen P53><Chemokine (C-X-C Motif) Ligand 12><Chronic Granulocytic Leukemia><Chronic Myelocytic Leukemia><Chronic Myelogenous Leukemia><Chronic Myeloid Leukemia><D-Glucose><Deacetylase><Deacetylation><Development><Dextrose><Disease><Disease remission><Disorder><Drug resistance><EPH- and ELK-Related Tyrosine Kinase><EPH-and ELK-Related Kinase><Ephrin Type-A Receptor 8><Ephrin Type-A Receptor 8 Precursor><Fatty Acids><Financial Hardship><Gene Combinations><Gene Expression><General Transcription Factor Gene><General Transcription Factors><Generations><Gln><Glucose><Glutamine><Glycolysis><Goals><HSC quiescence><Hematologic Cancer><Hematologic Malignancies><Hematologic Neoplasms><Hematological Malignancies><Hematological Neoplasms><Hematological Tumor><Hematopoietic Cancer><Hematopoietic Progenitor Cells><Hematopoietic stem cells><In Vitro><Intermediary Metabolism><Intracellular Communication and Signaling><Knowledge><L-Glutamine><Label><Leukemic progenitor and stem cell><Maintenance><Malignant Hematologic Neoplasm><Malignant Neoplasms><Malignant Tumor><Metabolic><Metabolic Pathway><Metabolic Processes><Metabolism><Mitochondria><Mitochondrial Proteins><Natural regeneration><Oncoprotein p53><Oxidative Phosphorylation><Oxidative Phosphorylation Pathway><Oxygen Radicals><P53><PBSF><PPAR alpha><PPAR-α><PPARalpha><PPARα><PTK Inhibitors><Patients><Peroxisome Proliferator-Activated Receptor alpha><Peroxisome Proliferator-Activated Receptor α><Phosphoprotein P53><Phosphoprotein pp53><Play><Pre-B Cell Growth Stimulating Factor><Pro-Oxidants><Process><Proliferating><Protein TP53><Protein Tyrosine Kinase><Protein Tyrosine Kinase EEK><Protein Tyrosine Kinase Inhibitors><Q Levoglutamide><Q. Levoglutamide><Reactive Oxygen Species><Regeneration><Regulation><Relapse><Remission><Remission Induction><Research><Resistance><Respiration><Risk><Role><SCYB12><SDF-1><SDF-1A><SDF-1B><SDF-1alpha><SDF1><SDF1A><SDF1B><SIRT1><SIRT1 gene><Sdf1 protein><Signal Transduction><Signal Transduction Systems><Signaling><Sirtuin 1><Stromal Cell-Derived Factor 1><Subcellular Process><TK Inhibitors><TLSF-A><TLSF-B><TP53><TP53 gene><TPAR1><TRP53><Toxic effect><Toxicities><Transcription Activator><Transcription Coactivator><Transcription Factor Coactivator><Transcription Factor Proto-Oncogene><Transcription factor genes><Transcriptional Activator><Transcriptional Activator/Coactivator><Transcriptional Coactivator><Translations><Tumor Protein p53><Tumor Protein p53 Gene><Tyrosine Kinase><Tyrosine Kinase Inhibitor><Tyrosine-Protein Kinase Receptor EEK><Tyrosine-Specific Protein Kinase><Tyrosylprotein Kinase><biological signal transduction><blood cell progenitor><blood progenitor><blood stem cell><blood stem cell quiescence><blood-forming stem cell><cell metabolism><cell transformation><cellular metabaolism><cofactor><developmental><drug resistant><extracellular><fatty acid oxidation><financial adversity><financial burden><financial distress><financial insecurity><financial strain><financial stress><hIRH><hematopoietic progenitor><hematopoietic stem cell quiescence><hematopoietic stem progenitor cell><hemopoietic progenitor><hemopoietic stem cell><hydroxyaryl protein kinase><improved><improved outcome><in vivo><inhibitor><leukemia><leukemia treatment><leukemic progenitor><leukemic stem cell><leukemic therapy><malignancy><mesenchymal stromal cell><mitochondrial><mitochondrial metabolism><necrocytosis><neoplasm/cancer><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><overexpress><overexpression><oxidation><p53 Antigen><p53 Genes><p53 Tumor Suppressor><preservation><progenitor Cell growth><progenitor cell fate><progenitor cell function><progenitor cell population><progenitor fate><progenitor function><progenitor growth><progenitor population><protein p53><regenerate><resistance to Drug><resistance to therapy><resistant><resistant to Drug><resistant to therapy><respiratory mechanism><response><restoration><self-renew><self-renewal><social role><stem and progenitor cell fate><stem and progenitor cell function><stem and progenitor cell population><stem and progenitor function><stem cell fate><stem cell function><stem cell growth><stem cell population><stromal cell-derived factor-1alpha><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic resistance><therapy resistant><transcription co-activator><transcription factor><transcriptional co-activator><transformed cells><translation><treatment resistance><tyrosyl protein kinase>