Human Philadelphia chromosome-positive (Ph+) leukemias are induced by the BCR-ABL oncogene (P190 or P210) and include two distinct diseases: B-cell acute lymphoblastic leukemia (B-ALL) and chronic myeloid leukemia (CML). Compare to CML that responds well to BCR-ABL tyrosine kinase inhibitors (TKIs), BCR-ABL-positive B-ALL only has a short-lived therapeutic response to available TKIs and has a poor prognosis. B-ALL can be initially induced by P190BCR-ABL and advanced from chronic phase CML often induced by P210BCR-ABL. Less sensitivity of B-ALL to TKIs even in the absence of BCR-ABL kinase mutations suggests that there must be critical pathways whose activation by BCR-ABL is required for B-ALL development but cannot be completely shut down through a sole inhibition of BCR-ABL kinase activity by TKIs. It also suggests that TKIs do not completely eradicate B-ALL-initiating cells responsible for disease initiation and insensitive to chemotherapy. There is an urgent need for developing new therapeutic strategies synergistic with available treatments, aiming at targeting B-ALL-initiating cells to achieve a cure. In this regard, we have obtained preliminary results showing that arachidonate 15-lipoxygenase (Alox15) is a critical gene upregulated in B-ALL cells by BCR-ABL and required for B-ALL development in mice. In theory, B-ALL is derived from B-ALL-initiating cells, leading us to hypothesize that Alox15 represents a critical genetic pathway required for B-ALL and may serve as a target for eradicating B-ALL- initiating cells to more effectively treat B-ALL. Although we previously showed that Alox15 plays a role in BCR-ABL-induced CML, BCR-ABL-induced B-ALL is a distinct disease with a poor response to TKIs compared to CML. Also, BCR-ABL utilizes distinct signaling pathways or share some pathways but utilize them differently during leukemogenesis. More importantly, the role of Alox15 in human B-ALL is totally unknown. It will be critical and necessary to study the role of Alox15 in vivo using primary human B-ALL cells and to propose in-depth mechanistic studies to fully understand the Alox15 pathway that contributes to survival regulation of B-ALL-initiating cells, B-ALL development and TKI resistance. Therefore, we propose the following two specific aims are: 1) To study the role of Alox15 in survival regulation of B-ALL-initiating cells and in TKI resistance using mouse and primary human BCR-ABL-positive B-ALL cells; and 2) To dissect genetic pathways mediating Alox15 signaling and function in B-ALL-initiating cells and during B-ALL development. If successful, the results will have a huge impact on our understanding of human BCR-ABL- positive B-ALL for identifying novel targets in treating human B-ALL that still lacks effective therapies.
(Relevance) Human BCR-ABL-positive B-cell acute lymphonblastic leukemia (B-ALL) has a poor prognosis and short- lived response to chemotherapy, which is likely related to B-ALL-initiating cells; the underlying mechanisms are unknown. There is an urgent need for identifying new target genes in B-ALL cells for treating BCR-ABL- positive B-ALL. We have discovered that a gene (called Alox15) plays a critical role in B-ALL development, and we believe it will be important to further study the role of Alox15 in human B-ALL-initiating cells and B- ALL development, and to fully understand mechanistically how Alox15 contributes to B-ALL initiation and drug resistance for developing novel strategies in treating human B-ALL that still lacks effective therapies.