The main challenge in the therapy of Acute Lymphocytic Leukemia (ALL) is overcoming resistance to chemotherapy. We have found that the hypoxic bone marrow niche in ALL is greatly expanded compared to normal hematopoiesis. Our preliminary data strongly indicate role for the hypoxic bone marrow microenvironment in chemoresistance of ALL cells. Further evidence for the role of hypoxia is our finding that the Hypoxia-Inducible Factor-11 (HIF-11) protein is highly expressed in 68% of primary ALL samples, while it is only sparingly expressed in normal bone marrow (BM). Our preliminary data indicate that hypoxia, via induction of the transcription factor HIF-11, promotes the switch to glycolytic metabolism and upregulates chemokines, each contributing to the resistance of leukemic cells in BM niches. The central hypothesis is that hypoxic niches within the BM microenvironment promote leukemia cell survival and confer chemoresistance.
In Aim 1, we will characterize molecular determinants of chemoresistance of leukemic blasts grown under hypoxic conditions of the BM microenvironment. The functional role of HIF-11 and its downstream targets will be determined through utilization of knock-down approaches with siRNA and/or genetically engineered mice.
In Aim 2, we will dissect the role of hypoxia and HIF-11 in the BM microenvironment niches of ALL, both in vitro and in vivo.
In Aim 3, we propose to develop novel noninvasive imaging to study the dynamics of stroma-leukemia interactions and the functional role of HIF-11 in the hypoxic BM niches in vivo. Studies proposed here will for the first time investigate hypoxia as an essential component of the leukemic microenvironment and determine downstream mediators of chemoresistance. Our preliminary evidence strongly suggests that targeting hypoxia may be feasible and may render leukemic cells drug sensitive. Since both, HIF-11 inhibitors and hypoxia-activated pro-drugs are in early stages of clinical development;these studies will provide the foundation for future clinical trials with these agents in leukemia. Further, imaging techniques validated in the in vivo leukemia models will be applicable in the human trials and may allow to identify patients that could benefit from these approaches. To this end, we have successfully labeled a target- specific agent with an optical reporter and demonstrated binding of this agent to the hypoxic leukemia cells. We anticipate that understanding of the complex interactions between ALL cells and their microenvironment will provide mechanism-based rationale for eliminating resistant ALL progenitor cells.
Narrative Studies proposed here will for the first time investigate hypoxia as an essential component of the leukemic microenvironment and determine downstream mediators of chemoresistance. Our preliminary evidence strongly suggests that targeting hypoxia may be feasible and may render leukemic cells drug sensitive. We anticipate that understanding of the complex interactions between ALL cells and their microenvironment will provide mechanism-based rationale for eliminating resistant ALL progenitor cells and provide the foundation for future clinical trials with HIF-11 inhibitors and hypoxia-activated pro-drugs.
|Benito, Juliana; Ramirez, Marc S; Millward, Niki Zacharias et al. (2016) Hypoxia-Activated Prodrug TH-302 Targets Hypoxic Bone Marrow Niches in Preclinical Leukemia Models. Clin Cancer Res 22:1687-98|
|Harada, Masako; Benito, Juliana; Yamamoto, Shinichi et al. (2015) The novel combination of dual mTOR inhibitor AZD2014 and pan-PIM inhibitor AZD1208 inhibits growth in acute myeloid leukemia via HSF pathway suppression. Oncotarget 6:37930-47|
|Tabe, Yoko; Konopleva, Marina (2015) Role of Microenvironment in Resistance to Therapy in AML. Curr Hematol Malig Rep 10:96-103|
|Lu, Hongbo; Kojima, Kensuke; Battula, Venkata Lokesh et al. (2014) Targeting connective tissue growth factor (CTGF) in acute lymphoblastic leukemia preclinical models: anti-CTGF monoclonal antibody attenuates leukemia growth. Ann Hematol 93:485-92|
|Jacamo, Rodrigo; Chen, Ye; Wang, Zhiqiang et al. (2014) Reciprocal leukemia-stroma VCAM-1/VLA-4-dependent activation of NF-ÎºB mediates chemoresistance. Blood 123:2691-702|
|Chen, Ye; Jacamo, Rodrigo; Konopleva, Marina et al. (2013) CXCR4 downregulation of let-7a drives chemoresistance in acute myeloid leukemia. J Clin Invest 123:2395-407|
|Jin, Linhua; Tabe, Yoko; Lu, Hongbo et al. (2013) Mechanisms of apoptosis induction by simultaneous inhibition of PI3K and FLT3-ITD in AML cells in the hypoxic bone marrow microenvironment. Cancer Lett 329:45-58|
|VÃ©lez, Juliana; Hail Jr, Numsen; Konopleva, Marina et al. (2013) Mitochondrial uncoupling and the reprograming of intermediary metabolism in leukemia cells. Front Oncol 3:67|
|Battula, V Lokesh; Chen, Ye; Cabreira, Maria da Graca et al. (2013) Connective tissue growth factor regulates adipocyte differentiation of mesenchymal stromal cells and facilitates leukemia bone marrow engraftment. Blood 122:357-66|
|Jin, Linhua; Tabe, Yoko; Kojima, Kensuke et al. (2013) PI3K inhibitor GDC-0941 enhances apoptotic effects of BH-3 mimetic ABT-737 in AML cells in the hypoxic bone marrow microenvironment. J Mol Med (Berl) 91:1383-97|
Showing the most recent 10 out of 14 publications