Identification of new targets and novel treatment strategies for chronic myeloid leukemia. Ralph B. Arilnahaus. Ph.D.- My laboratory has published new information on several key proteins in chronic myelogenous leukemia that are regulated by the Bcr-Abl oncoprotein. These proteins are lipocalin 2 (NGAL/24p3), Jak2 and Bcr. We were first to discover the role of lipocalin 2 in Bcr-Ab1 induced leukemia. Our recent studies with 24p3 null mice showed that 24p3 secretion by Bcr-Abl+ cells is a requirement for leukemia induction by Bcr-Abl in a mouse model. Regarding Jak2, we show that it is part of a large signaling network. Inhibition of Jak2 induces apoptosis in imatinib-sensitive/resistant Bcr-Abl + cells, in CML cell lines and in cells from blast crisis CML patients. Concerning Bcr, wild-type Bcr protein inhibits the oncogenic function of Bcr-Abl but serine/threonine kinase-defective Bcr enhances the oncogenic effects of Bcr-Abl.
Aim #1, Develop a monoclonal antibody that blocks lipocalin 2 (NGAL/24p3) activities induced by Bcr-Abl, and investigate the effects in mouse leukemia models. Our goal is to interfere with NGAL function for treatment of CML in combination with other therapeutic regimens such as Gleevec therapy.
Aim #2, Investigate the mechanistic effects of new Jak2 inhibitors in imatinib-sensitive and resistant CML cell lines, patient cells, and in patient cells from advanced stages of CML with the long-term goal of doing clinical trials in imatinib-resistant CML and late stage CML (with Dr. Cortes). We hypothesize that a potent Jak2 inhibitor will be useful in the treatment of drug-resistant CML as well as in all stages of CML because of the dominant role of Jak2 in oncogenic signaling in CML cells. We have identified a new Jak2 inhibitor (WP1193) that disrupts the Bcr-Abl/Jak2/HSP90 signaling network complex leading to apoptosis of drug-resistant CML cells and blast crisis CML cells. Surprisingly, preliminary results indicate that the Jak2 kinase phosphorylates Tyr 177 of Bcr-Abl, which upon Jak2 inhibition drastically reduced Grb2 binding to the network complex and caused the disruption of the Ras and PI-3 kinase signaling pathways. Importantly, Jak2 inhibition also drastically reduced Bcr-Abl protein levels, causing down-regulafion of STAT5 and STAT3 signaling. Thus, Jak2 inhibition disrupts many If not all oncogenic effects in CML.
Aim #3, Invesfigate the role ofthe Bcr Ser/Thr kinase in regulating Bcr-Abl oncogenic activity. We will search for mutations in the Bcr kinase domain, as we hypothesize that such mutations play a role in CML disease progression.

Public Health Relevance

The outcome of these studies will lead to new strategies to treat drug-resistant forms of chronic myeloid leukemia and advanced stages of CML. Each strategy was based on published research generated by the Ariinghaus lab over the last five years of support from this P01 grant and a ROI grant from NIH.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas MD Anderson Cancer Center
United States
Zip Code
Ruvolo, Peter P; Ruvolo, Vivian R; Burks, Jared K et al. (2018) Role of MSC-derived galectin 3 in the AML microenvironment. Biochim Biophys Acta Mol Cell Res 1865:959-969
Cortes, Jorge E; Gambacorti-Passerini, Carlo; Deininger, Michael W et al. (2018) Bosutinib Versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia: Results From the Randomized BFORE Trial. J Clin Oncol 36:231-237
Sasaki, Koji; Kantarjian, Hagop; O'Brien, Susan et al. (2018) Prediction for sustained deep molecular response of BCR-ABL1 levels in patients with chronic myeloid leukemia in chronic phase. Cancer 124:1160-1168
Gambacorti-Passerini, Carlo; Cortes, Jorge E; Lipton, Jeff H et al. (2018) Safety and efficacy of second-line bosutinib for chronic phase chronic myeloid leukemia over a five-year period: final results of a phase I/II study. Haematologica 103:1298-1307
Boddu, Prajwal; Shah, Abdul Rashid; Borthakur, Gautam et al. (2018) Life after ponatinib failure: outcomes of chronic and accelerated phase CML patients who discontinued ponatinib in the salvage setting. Leuk Lymphoma 59:1312-1322
Kornblau, Steven M; Ruvolo, Peter P; Wang, Rui-Yu et al. (2018) Distinct protein signatures of acute myeloid leukemia bone marrow-derived stromal cells are prognostic for patient survival. Haematologica 103:810-821
Zhang, Weiguo; Ly, Charlie; Ishizawa, Jo et al. (2018) Combinatorial targeting of XPO1 and FLT3 exerts synergistic anti-leukemia effects through induction of differentiation and apoptosis in FLT3-mutated acute myeloid leukemias: from concept to clinical trial. Haematologica 103:1642-1653
Alhuraiji, Ahmad; Kantarjian, Hagop; Boddu, Prajwal et al. (2018) Prognostic significance of additional chromosomal abnormalities at the time of diagnosis in patients with chronic myeloid leukemia treated with frontline tyrosine kinase inhibitors. Am J Hematol 93:84-90
Ishizawa, Jo; Nakamaru, Kenji; Seki, Takahiko et al. (2018) Predictive Gene Signatures Determine Tumor Sensitivity to MDM2 Inhibition. Cancer Res 78:2721-2731
Boddu, Prajwal; Benton, Christopher B; Wang, Wei et al. (2018) Erythroleukemia-historical perspectives and recent advances in diagnosis and management. Blood Rev 32:96-105

Showing the most recent 10 out of 375 publications