The goal of the CALGB Leukemia Correlative Sciences Committee (LCSC) is to attain a highly successful integration of correlative laboratory studies into the design and implementation of CALGB leukemia clinical trials. During the current reporting period (6/1/02-5/31/08), members of this Committee discovered and/or validated multiple prognostic molecular and cytogenetic markers that can be used for risk-adapted patients'stratification into clinical trials and/or be regarded as therapeutic targets. The scientific progress made by the LCSC during the current reporting period is supported by 162 publications (70 manuscripts and 92 abstracts published or in press). To continue this work, in this competing renewal application, the CALGB LCSC is requesting support for three established Cores (Core A: Cytogenetics;Core B: Leukemia Tissue Banking;Core C: Administration) and four projects, each of which utilizes material from patients that are enrolled on CALGB leukemia treatment protocols. A common theme of this proposal is the integration of the established prognostic markers with newly discovered markers, including genome-wide gene copy alterations and gene and microRNA expression profiles, to dissect acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL) into molecular subsets for which response to treatment and clinical outcome can be predicted. Furthermore, accumulating data indicate that certain subpopulations of AML cells have high proliferative potential and self-renewal capacity similar to normal stem cells and therefore could mediate resistance to anti-leukemia chemotherapy. This Committee will pursue for the first time a relatively novel strategy to test the relevance of abundance and gene profiles of these so-called leukemia stem cells (LSCs) to treatment response and clinical outcome of AML patients. Thus, with the support of the Cytogenetics core and the Leukemia Tissue Bank, each of the four projects will address scientific questions that correlate cytogenetic and molecular findings with leukemia patients'diagnosis, response to treatment and survival. The projects, led by outstanding leaders in the field of leukemia biology, diagnosis, and treatment are: Project 1: "Molecular characterization of adult AML" (PI Bloomfield/Marcucci,) Project 2: "Functional and genomic characterization of leukemia stem cells in AML" (PI Armstrong) Project 3: "Genome-wide analysis of adult ALL" (PI Downing) Project 4:"Molecular, biochemical, and immunologic studies of early state and symptomatic CLL" (PI Byrd).

Public Health Relevance

The ultimate goal of the CALGB LCSC is to improve the cure of leukemia. By integrating the biologic and prognostic findings derived from the research plan outlined in this proposal, we intend to devise risk stratification schemas that select personalized treatments according to the genetic make up of the patients'diseases and, thereby, improve patients'survival.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Cooperative Clinical Research--Cooperative Agreements (U10)
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Subcommittee G - Education (NCI)
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Mooney, Margaret M
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Ohio State University
Internal Medicine/Medicine
Schools of Medicine
United States
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Niederwieser, C; Kohlschmidt, J; Volinia, S et al. (2015) Prognostic and biologic significance of DNMT3B expression in older patients with cytogenetically normal primary acute myeloid leukemia. Leukemia 29:567-75
Marcucci, Guido; Yan, Pearlly; Maharry, Kati et al. (2014) Epigenetics meets genetics in acute myeloid leukemia: clinical impact of a novel seven-gene score. J Clin Oncol 32:548-56
Eisfeld, Ann-Kathrin; Schwind, Sebastian; Patel, Ravi et al. (2014) Intronic miR-3151 within BAALC drives leukemogenesis by deregulating the TP53 pathway. Sci Signal 7:ra36
Becker, H; Maharry, K; Mrózek, K et al. (2014) Prognostic gene mutations and distinct gene- and microRNA-expression signatures in acute myeloid leukemia with a sole trisomy 8. Leukemia 28:1754-8
Alachkar, Houda; Santhanam, Ramasamy; Maharry, Kati et al. (2014) SPARC promotes leukemic cell growth and predicts acute myeloid leukemia outcome. J Clin Invest 124:1512-24
Wetzler, Meir; Watson, Dorothy; Stock, Wendy et al. (2014) Autologous transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia achieves outcomes similar to allogeneic transplantation: results of CALGB Study 10001 (Alliance). Haematologica 99:111-5
Havelange, Violaine; Ranganathan, Parvathi; Geyer, Susan et al. (2014) Implications of the miR-10 family in chemotherapy response of NPM1-mutated AML. Blood 123:2412-5
Kolitz, Jonathan E; George, Stephen L; Benson Jr, Don M et al. (2014) Recombinant interleukin-2 in patients aged younger than 60 years with acute myeloid leukemia in first complete remission: results from Cancer and Leukemia Group B 19808. Cancer 120:1010-7
Whitman, S P; Kohlschmidt, J; Maharry, K et al. (2014) GAS6 expression identifies high-risk adult AML patients: potential implications for therapy. Leukemia 28:1252-8
Roberts, Kathryn G; Li, Yongjin; Payne-Turner, Debbie et al. (2014) Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med 371:1005-15

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