BCR/ABL fusion tyrosine kinase results from t(9;22) reciprocal chromosomal translocation and is leukemogenic only when expressed in a hematopoietic stem cells (HSCs) with self-renewal capacity thereby inducing leukemia stem cell (LSC). LSCs are capable to generate large numbers of leukemic progenitor cells (LPCs), which cannot self-renew and eventually differentiate to mature elements, causing chronic myelogenous leukemia in chronic phase (CML-CP). CML-CP is a relatively benign stem cell-derived but a progenitor-driven disease. In the experimental models BCR/ABL kinase promotes ROS-dependent genomic instability, which may lead to resistance to ABL kinase inhibitor imatinib mesylate (IM), and to malignant progression of CML- CP to aggressive blast crisis (CML-BC). Resistance to IM is often caused by mutations encoding amino acid substitutions in BCR/ABL kinase. Malignant progression from CML-CP to CML-BC is associated with accumulation of additional chromosomal aberrations. Resistance to the inhibitors and malignant progression are the major problems in BCR/ABL-positive leukemias. IM-resistant BCR/ABL mutants are detected in stem and early progenitor -enriched pools, which may display different leukemogenic capability and higher likelihood of accumulation of additional mutations associated with resistance to novel tyrosine kinase inhibitors. Therefore the main goals of this application are to determine if ROS-induced genomic instability (1) originate in LSCs or in LPCs, and (2) is further enhanced in CML cells expressing IM-resistant BCR/ABL mutants. For this reason ROS levels and oxidative DNA damage will be examined and compared in LSCs and LPCs from CML-CP and CML-BC patients carrying BCR/ABL wild-type or IM-resistant mutant, and in HSCs and progenitors from healthy donors, using immunofluorescent and biochemical approaches. IM-resistant BCR/ABL kinase point-mutants and chromosomal aberrations will be examined and compared in LSCs and LPCs harvested from immunodeficient NOG mice inoculated with CML-CP and CML-BC patient cells carrying BCR/ABL wild-type and IM-resistant mutants, which were kept under standard or reduced oxidative stress. Identification of ROS as causative element for oxidative DNA damage leading to genomic instability in LSCs and/or LPCs expressing BCR/ABL wild-type or IM-resistant mutant should have a significant impact on general understanding of the disease, potential use of anti-oxidants combined with IM as therapeutic agents, and targeting the particular leukemia cell sub-population in future investigations of the mechanisms generating ROS and/or compromising the fidelity of DNA repair.
BCR/ABL oncogenic tyrosine kinase transforms hematopoeitic stem cells (HSCs) into leukemia stem cells (LSCs) and induces chronic myeloid leukemia in chronic phase (CML-CP). LSCs are capable to generate large numbers of leukemic progenitors (LPCs), which eventually differentiate to mature elements. However, BCR/ABL promotes additional genetic changes causing resistance to ABL kinase inhibitor imatinib mesylate (IM), and malignant progression of CML-CP to the aggressive blast crisis (CML-BC). The main goal of this application is to determine if these problems originate in LSCs or in LPCs and if IM-resistant CML cells display higher susceptibility to accumulate additional mutations. These studies will break ground toward new directions in studying LSCs in CML and other leukemias, and in testing of novel therapeutic strategies.
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