Chronic myeloid leukemia (CML) is caused by BCR-ABL1, a constitutively active tyrosine kinase. The development of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 has revolutionized the treatment of CML, turning it from a fatal into a manageable chronic condition. Many patients respond favorably to TKIs, but some patients do not achieve a response, and others lose their response, for an overall estimated failure rate of 20- 30% in chronic phase (CP-CML), and even higher rates in advanced CML. While TKI resistance is commonly linked to point mutations in the BCR-ABL1 kinase domain, ~50% of clinical resistance cannot be explained by BCR-ABL1 mutations, suggesting BCR-ABL1 kinase-independent resistance. Recurrence of active CML after discontinuation of TKIs in responding patients is thought to reflect persistence of quiescent leukemic stem cells (LSCs) that are innately resistant to TKIs despite BCR-ABL1 inhibition. Thus, understanding the molecular mechanisms underlying BCR-ABL1 kinase-independent resistance will be critical to identify alternative treatment strategies for patients with TKI resistance or advanced CML and to eradicate disease. Microarray data revealed downregulation of G0S2 mRNA expression in CML CD34+ cells from imatinib non-responders (without mutations) compared to responders, and in advanced disease compared to chronic phase. Preliminary data suggests that G0S2 may play a role in both primary TKI resistance and in blastic transformation of CML.
Specific Aim 1 : Determine whether G0S2 loss promotes TKI resistance and disease progression in CML. Data from this aim will investigate the functional consequence of G0S2 loss in TKI resistance and blastic transformation. We will assess the role of G0S2 in the growth, survival, and TKI sensitivity of CML cell lines and primary CML CD34+ cells both in vitro and in vivo. We will also utilize a BCR-ABL1 transgenic mouse model and G0S2 null mice to assess the role of G0S2 in CML leukemogenesis in vivo.
Specific Aim 2 : Identify the mechanism by which loss of G0S2 induces TKI resistance in CML. G0S2 has been implicated in metabolic pathway regulation, including fatty acid synthesis and oxidative phosphorylation. We have formed a collaborative research team to rigorously establish the mechanistic role of G0S2 downregulation in TKI resistance. We will address how reduced expression of G0S2 influences these metabolic pathways and, in turn, whether these pathways alter imatinib response.
Specific Aim 3 : Determine the mechanism(s) by which G0S2 is downregulated in TKI resistance and identify strategies to restore G0S2 expression. Data from this aim will identify how G0S2 is downregulated in TKI resistance and blastic transformation, and will identify ways of reprogramming TKI-resistant cells into a TKI-sensitive phenotype. We will investigate the potential role of promoter hypermethylation and binding of transcriptional repressors, as well as the contribution of known oncogenic signaling pathways. These studies will be crucial for developing novel treatment approaches for TKI- resistant CML patients and other drug-resistant leukemias, and will launch my independent research career.

Public Health Relevance

Tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 have turned chronic myeloid leukemia (CML) from a fatal to a chronic disease. Despite improved survival, resistance is a clinical problem, and TKIs do not target the CML leukemic stem cell (LSC), meaning that patients must be treated for life at a high economic burden and sometimes despite significant side effects. Understanding the molecular mechanisms allowing for TKI resistance despite BCR-ABL1 inhibition, as well as survival of LSCs, is a central goal of this proposal, and will identify potential treatment strategies aimed at targeting TKI-resistant patients and eradicating disease.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Career Transition Award (K22)
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Subcommittee I - Career Development (NCI)
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Jakowlew, Sonia B
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Texas Tech University
Other Basic Sciences
Schools of Medicine
United States
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