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Grant Details

Grant Number: 5R01CA136537-05 Interpret this number
Primary Investigator: Malek, Sami
Organization: University Of Michigan
Project Title: Genomic Complexity and Clinical Outcome in Chronic Lymphocytic Leukemia
Fiscal Year: 2013
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Abstract

DESCRIPTION (provided by applicant): CLL is the most common leukemia in the Western world. Diagnosis and staging of the disease is made by clinical and laboratory findings. The clinical course of the disease is highly variable, and treatment and prognostic variables are continuously being refined. Identification of biomarkers that identify the most aggressive CLL subtypes is a research priority as it is these patients that carry a disproportional share of the burden of CLL mortality. Of the currently known biomarkers, only the relatively rare del17p (5%-7% of all CLL cases at diagnosis) identifies patients with high risk for death within years of diagnosis. Identification of del17p is therefore of substantial importance in CLL disease management and has resulted in the development of risk-adapted therapy approaches to CLL. Unlike acute myelogenous leukemia, where karyotypic changes play a dominant role in the appropriate selection of therapy, in CLL, therapy and counseling based on genetic lesions are still being developed and refined. Genomic changes in CLL have been difficult to study comprehensively, as CLL cells do not grow well ex vivo. A major technical breakthrough, therefore, has been the application of interphase fluorescent in situ hybridization to the study of CLL genomes, which delineated five prognostically significant chromosomal aberrations: del13q14 (about 50%), del11q22-q23 (~10%), trisomy 12 (~15-20%), del17p13 (~5-7%) and del6q21. Interphase FISH is now used in clinical practice to risk-stratify CLL patients and presence of del17p or del11q has identified a subgroup of CLL patients with poor response duration to standard therapy. Despite the importance of FISH testing in CLL, this technique has significant shortcomings. One of the most prominent caveats is the biased assessment of the genome and consequently the inability to reliably detect CLL with multiple chromosomal abnormalities (CLL with complex karyotypes). To overcome these difficulties in CLL genome analysis, we and others have employed SNP-arrays to characterize the CLL genome at high resolution. One outcome of this analysis has been the discovery and initial characterization of a subgroup of CLL patients (~15-40%) with multiple sub-chromosomal losses and gains (high genomic complexity) that display very rapid disease progression and poor response duration to standard therapies. In this proposal, we wish to extend our initial observation on CLL patients with high genomic complexity to fully explore the clinical significance of this observation and to derive initial insights into the molecular mechanisms of this phenomenon. We anticipate that through these studies, CLL patients with high genomic complexity will be confirmed to be of high risk for early need of therapy and for poor response to conventional therapy resulting in untimely death, thus identifying a substantial subpopulation of very high risk CLL patients towards which new drug development should be targeted and to which refined counseling should be applied.

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Publications

Genetics of follicular lymphoma transformation.
Authors: Pasqualucci L, Khiabanian H, Fangazio M, Vasishtha M, Messina M, Holmes AB, Ouillette P, Trifonov V, Rossi D, Tabḅ F, Ponzoni M, Chadburn A, Murty VV, Bhagat G, Gaidano G, Inghirami G, Malek SN, Rabadan R, Dalla-Favera R
Source: Cell Rep, 2014 Jan 16;6(1), p. 130-40.
EPub date: 2014 Jan 2.
PMID: 24388756
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Molecular biomarkers in chronic lymphocytic leukemia.
Authors: Malek S
Source: Adv Exp Med Biol, 2013;792, p. 193-214.
PMID: 24014298
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Health-related quality of life, lifestyle behaviors, and intervention preferences of survivors of childhood cancer.
Authors: Badr H, Chandra J, Paxton RJ, Ater JL, Urbauer D, Cruz CS, Demark-Wahnefried W
Source: J Cancer Surviv, 2013 Dec;7(4), p. 523-34.
EPub date: 2013 Jun 8.
PMID: 23749663
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Clonal evolution, genomic drivers, and effects of therapy in chronic lymphocytic leukemia.
Authors: Ouillette P, Saiya-Cork K, Seymour E, Li C, Shedden K, Malek SN
Source: Clin Cancer Res, 2013 Jun 1;19(11), p. 2893-904.
EPub date: 2013 Apr 25.
PMID: 23620403
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The biology and clinical significance of acquired genomic copy number aberrations and recurrent gene mutations in chronic lymphocytic leukemia.
Authors: Malek SN
Source: Oncogene, 2013 Jun 6;32(23), p. 2805-17.
EPub date: 2012 Sep 24.
PMID: 23001040
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Incidence and clinical implications of ATM aberrations in chronic lymphocytic leukemia.
Authors: Ouillette P, Li J, Shaknovich R, Li Y, Melnick A, Shedden K, Malek SN
Source: Genes Chromosomes Cancer, 2012 Dec;51(12), p. 1125-32.
EPub date: 2012 Sep 6.
PMID: 22952040
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Characteristics of chronic lymphocytic leukemia with somatically acquired mutations in NOTCH1 exon 34.
Authors: Shedden K, Li Y, Ouillette P, Malek SN
Source: Leukemia, 2012 May;26(5), p. 1108-10.
EPub date: 2011 Dec 20.
PMID: 22182918
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Health behaviors and weight status of childhood cancer survivors and their parents: similarities and opportunities for joint interventions.
Authors: Badr H, Paxton RJ, Ater JL, Urbauer D, Demark-Wahnefried W
Source: J Am Diet Assoc, 2011 Dec;111(12), p. 1917-23.
PMID: 22117669
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The prognostic significance of various 13q14 deletions in chronic lymphocytic leukemia.
Authors: Ouillette P, Collins R, Shakhan S, Li J, Li C, Shedden K, Malek SN
Source: Clin Cancer Res, 2011 Nov 1;17(21), p. 6778-90.
EPub date: 2011 Sep 2.
PMID: 21890456
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Acquired genomic copy number aberrations and survival in chronic lymphocytic leukemia.
Authors: Ouillette P, Collins R, Shakhan S, Li J, Peres E, Kujawski L, Talpaz M, Kaminski M, Li C, Shedden K, Malek SN
Source: Blood, 2011 Sep 15;118(11), p. 3051-61.
EPub date: 2011 Jul 27.
PMID: 21795749
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Sequence analysis of 515 kinase genes in chronic lymphocytic leukemia.
Authors: Zhang X, Reis M, Khoriaty R, Li Y, Ouillette P, Samayoa J, Carter H, Karchin R, Li M, Diaz LA Jr, Velculescu VE, Papadopoulos N, Kinzler KW, Vogelstein B, Malek SN
Source: Leukemia, 2011 Dec;25(12), p. 1908-10.
EPub date: 2011 Jun 24.
PMID: 21701494
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A pathobiological role of the insulin receptor in chronic lymphocytic leukemia.
Authors: Saiya-Cork K, Collins R, Parkin B, Ouillette P, Kuizon E, Kujawski L, Erba H, Campagnaro E, Shedden K, Kaminski M, Malek SN
Source: Clin Cancer Res, 2011 May 1;17(9), p. 2679-92.
EPub date: 2011 Feb 9.
PMID: 21307146
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Acquired genomic copy number aberrations and survival in adult acute myelogenous leukemia.
Authors: Parkin B, Erba H, Ouillette P, Roulston D, Purkayastha A, Karp J, Talpaz M, Kujawski L, Shakhan S, Li C, Shedden K, Malek SN
Source: Blood, 2010 Dec 2;116(23), p. 4958-67.
EPub date: 2010 Aug 20.
PMID: 20729466
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NF1 inactivation in adult acute myelogenous leukemia.
Authors: Parkin B, Ouillette P, Wang Y, Liu Y, Wright W, Roulston D, Purkayastha A, Dressel A, Karp J, Bockenstedt P, Al-Zoubi A, Talpaz M, Kujawski L, Liu Y, Shedden K, Shakhan S, Li C, Erba H, Malek SN
Source: Clin Cancer Res, 2010 Aug 15;16(16), p. 4135-47.
EPub date: 2010 May 26.
PMID: 20505189
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Multiple distinct molecular mechanisms influence sensitivity and resistance to MDM2 inhibitors in adult acute myelogenous leukemia.
Authors: Long J, Parkin B, Ouillette P, Bixby D, Shedden K, Erba H, Wang S, Malek SN
Source: Blood, 2010 Jul 8;116(1), p. 71-80.
EPub date: 2010 Apr 19.
PMID: 20404136
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Aggressive chronic lymphocytic leukemia with elevated genomic complexity is associated with multiple gene defects in the response to DNA double-strand breaks.
Authors: Ouillette P, Fossum S, Parkin B, Ding L, Bockenstedt P, Al-Zoubi A, Shedden K, Malek SN
Source: Clin Cancer Res, 2010 Feb 1;16(3), p. 835-47.
EPub date: 2010 Jan 19.
PMID: 20086003
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