The Philadelphia chromosome-positive (Ph+) leukemias, including chronic myeloid leukemia (CML) and Ph+ B- cell acute lymphoblastic leukemia (B-ALL), are prevalent blood cancers for which our current therapies are inadequate. While BCR-ABL1 tyrosine kinase inhibitors (TKIs) such as imatinib mesylate have replaced hematopoietic stem cell transplantation (HSCT) as initial therapy for CML, complete molecular remissions are rare and acquired resistance to TKI therapy is a significant clinical problem. Eligible Ph+ B-ALL patients undergo allogeneic HSCT in first remission following chemotherapy, but over half will relapse. Hence, it is likely that current therapy will not cure most Ph+ leukemia patients, and effective methods to eradicate residual leukemia are needed. To accomplish these goals, well-characterized mouse models of CML and B-ALL will be utilized to determine the mechanisms of pathogenesis of these diseases, to identify signaling pathways critical to leukemogenesis and to the genesis of leukemia-initiating or leukemia stem cels, and finally to validate these pathways as targets for therapy and conduct preclinical testing of molecularly targeted drugs. Together, these studies should yield important new knowledge that will improve the effectiveness of our current treatments for Ph+ leukemia, and increase the proportion of patients that are cured of their disease.

Public Health Relevance

Project Narrative Despite the advent of new "targeted" drugs for the treatment of blood cancer (leukemia), many patients will fail therapy and relapse. The goals of this proposal are to identify the ways that genetic changes in some types of leukemia actually cause the disease, using laboratory mice that are accurate representatives of the human disease. Identification of the ways leukemia is caused will lead to new approaches to treatment and ultimately cure of patients with leukemia.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA090576-12
Application #
8297923
Study Section
Special Emphasis Panel (ZRG1-BMCT-C (09))
Program Officer
Mufson, R Allan
Project Start
2001-04-01
Project End
2017-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
12
Fiscal Year
2012
Total Cost
$304,498
Indirect Cost
$112,990
Name
Tufts University
Department
Type
DUNS #
079532263
City
Boston
State
MA
Country
United States
Zip Code
02111
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Krause, Daniela S; Lazarides, Katherine; Lewis, Juliana B et al. (2014) Selectins and their ligands are required for homing and engraftment of BCR-ABL1+ leukemic stem cells in the bone marrow niche. Blood 123:1361-71
Joshi, Ila; Yoshida, Toshimi; Jena, Nilamani et al. (2014) Loss of Ikaros DNA-binding function confers integrin-dependent survival on pre-B cells and progression to acute lymphoblastic leukemia. Nat Immunol 15:294-304
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O'Callaghan, Katie; Lee, Lydia; Nguyen, Nga et al. (2012) Targeting CXCR4 with cell-penetrating pepducins in lymphoma and lymphocytic leukemia. Blood 119:1717-25
Walz, Christoph; Ahmed, Wesam; Lazarides, Katherine et al. (2012) Essential role for Stat5a/b in myeloproliferative neoplasms induced by BCR-ABL1 and JAK2(V617F) in mice. Blood 119:3550-60
Chan, Wayne W; Wise, Scott C; Kaufman, Michael D et al. (2011) Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036. Cancer Cell 19:556-68
Hu, Miaofen G; Deshpande, Amit; Schlichting, Nicolette et al. (2011) CDK6 kinase activity is required for thymocyte development. Blood 117:6120-31
Okimoto, Ross A; Van Etten, Richard A (2011) Navigating the road toward optimal initial therapy for chronic myeloid leukemia. Curr Opin Hematol 18:89-97
Van Etten, R A (2007) Aberrant cytokine signaling in leukemia. Oncogene 26:6738-49

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