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).
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.
|Eisfeld, Ann-Kathrin; Kohlschmidt, Jessica; Mrózek, Krzysztof et al. (2017) Mutational Landscape and Gene Expression Patterns in Adult Acute Myeloid Leukemias with Monosomy 7 as a Sole Abnormality. Cancer Res 77:207-218|
|Eisfeld, A-K; Kohlschmidt, J; Schwind, S et al. (2017) Mutations in the CCND1 and CCND2 genes are frequent events in adult patients with t(8;21)(q22;q22) acute myeloid leukemia. Leukemia 31:1278-1285|
|Eisfeld, A-K; Mrózek, K; Kohlschmidt, J et al. (2017) The mutational oncoprint of recurrent cytogenetic abnormalities in adult patients with de novo acute myeloid leukemia. Leukemia 31:2211-2218|
|Blum, W; Sanford, B L; Klisovic, R et al. (2017) Maintenance therapy with decitabine in younger adults with acute myeloid leukemia in first remission: a phase 2 Cancer and Leukemia Group B Study (CALGB 10503). Leukemia 31:34-39|
|Goyama, S; Schibler, J; Gasilina, A et al. (2016) UBASH3B/Sts-1-CBL axis regulates myeloid proliferation in human preleukemia induced by AML1-ETO. Leukemia 30:728-39|
|Niederwieser, Christian; Nicolet, Deedra; Carroll, Andrew J et al. (2016) Chromosome abnormalities at onset of complete remission are associated with worse outcome in patients with acute myeloid leukemia and an abnormal karyotype at diagnosis: CALGB 8461 (Alliance). Haematologica 101:1516-1523|
|DeBoer, Rebecca; Koval, Gregory; Mulkey, Flora et al. (2016) Clinical impact of ABL1 kinase domain mutations and IKZF1 deletion in adults under age 60 with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL): molecular analysis of CALGB (Alliance) 10001 and 9665. Leuk Lymphoma 57:2298-306|
|Walker, Alison R; Wang, Hongyan; Walsh, Katherine et al. (2016) Midostaurin, bortezomib and MEC in relapsed/refractory acute myeloid leukemia. Leuk Lymphoma 57:2100-8|
|Iacobucci, Ilaria; Li, Yongjin; Roberts, Kathryn G et al. (2016) Truncating Erythropoietin Receptor Rearrangements in Acute Lymphoblastic Leukemia. Cancer Cell 29:186-200|
|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|
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