Targeting Quiescence Pathways to Overcome Chemoresistance in EVI1-Overexpressing Leukemia

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PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML), an aggressive leukemia characterized by the excessive proliferation of abnormal myeloid progenitor cells in the bone marrow (BM), and carries a 5-year survival rate less than 25%. Overexpression of the oncogene ecotropic viral integration site 1 (EVI1) in AML is associated with shorter survival durations and higher relapse rates. AML-associated relapse is multifactorial, and previous studies have shown that the activation of cell cycle quiescence protects AML subclones during chemotherapy, resulting in their survival. Given the severity of EVI1-overexpressing AML, the lack of an in-depth understanding of the role of EVI1 in AML patients’ shorter survival durations and higher relapse rates, and the inadequacy of current therapeutic strategies, we aim to gain a better understanding of EVI1-associated chemoresistance with the long- term goal of developing novel therapies for this sever form of AML. Our preliminary studies using an EVI1- overexpressing AML mouse model and patient samples indicate that EVI1 overexpression activates quiescence pathways. Our ChIP-seq and ATAC-seq data revealed that the mechanism of EVI1-induced quiescence involves two pathways: 1) the upregulation of cyclin-dependent kinase inhibitor 1C (CDKN1C/P57kip2), a critical activator of hematopoietic stem cell quiescence, whose expression has been linked with AML relapse; and 2) the activation of purine-rich box binding protein 1 (PU.1), a master regulator of myelopoiesis, which is sufficient to trigger cell cycle quiescence in hematopoietic stem cells (HSCs). Thus, we hypothesize that EVI1 overexpression protects AML cells from chemotherapy by activating quiescence through CDKN1C and PU.1 pathways. To test our hypothesis, we will elucidate the mechanism of EVI1-induced CDKN1C expression and its role in quiescence (Aim 1), and investigate the role of PU.1 activation in EVI1-associated quiescence (Aim 2) in EVI1- overexpressing AML. This will be accomplished by integrating data from RNA-seq, ChIP-seq, ATAC-seq, and other techniques to analyze EVI1-overexpressing leukemia cells from our in vitro and in vivo models and from primary human AML samples. To translate the proposed mechanistic insights into clinical settings and therapeutic strategies, we will test new treatment regiments in preclinical studies using EVI1-overexpressing AML patient-derived xenograft (PDX) models (Aim 3). In summary, the proposed work will focus on investigating EVI1-induced quiescence mechanisms, and its findings will not only help explain the shorter survival durations and higher relapse rates associated with EVI1-overexpressing leukemia but also unveil new therapeutic strategies that reactivate the cell cycle and improve the survival of patients with EVI1-overexpressing AML.