Published online 10 March 2009
Haematologica, Vol 94, Issue 4, 518-527 doi:10.3324/haematol.2008.001347
Copyright © 2009 by Ferrata Storti Foundation

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Chronic Lymphocytic Leukemia

Molecular allelokaryotyping of T-cell prolymphocytic leukemia cells with high density single nucleotide polymorphism arrays identifies novel common genomic lesions and acquired uniparental disomy

Daniel Nowak^1,*, Emilie Le Toriellec^2,3,*, Marc-Henri Stern^2,3, Norihiko Kawamata¹, Tadayuki Akagi¹, Martin J. Dyer⁴, Wolf-Karsten Hofmann⁵, Seishi Ogawa^6,7,8, H. Phillip Koeffler¹

¹ Division of Hematology and Oncology, Cedars Sinai Medical Center, UCLA School of Medicine, Los Angeles, USA
² Institut Curie, Centre de Recherche, Paris, France
³ Inserm U830, Paris, France
⁴ Department of Hematology, University Hospitals, Leicester, United Kingdom
⁵ Department of Hematology and Oncology, Charité University Hospital, Campus Benjamin Franklin, Berlin, Germany
⁶ Department of Hematology and Oncology
⁷ Department of Cell Therapy and Transplantation Medicine and the 21^st century COE program, Graduate School of Medicine, University of Tokyo, Japan
⁸ Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Japan

Correspondence: Seishi Ogawa, Department of Regeneration Medicine for Hematopoiesis, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyoku, Tokyo 113-8655 Japan. E-mail:sogawa-tky{at}umin.ac.jp or Daniel Nowak, Division of Hematology and Oncology, Cedars Sinai Medical Center, UCLA School of Medicine, 8700 Beverly Blvd, Los Angeles, CA 90048, USA. E-mail:Daniel.Nowak{at}cshs.org

Background: T-cell prolymphocytic leukemia is a rare aggressive lymphoproliferative disease with a mature T-cell phenotype and characteristic genomic lesions such as inv(14)(q11q34), t(14;14)(q11;q32) or t(X;14)(q28;q11), mutation of the ATM gene on chromosome 11 and secondary alterations such as deletions of chromosome 8p and duplications of 8q.

Design and Methods: We analyzed malignant cells from 18 patients with T-cell prolymphocytic leukemia using high density 250K single nucleotide polymorphism arrays and molecular allelokaryotyping to refine understanding of known alterations and identify new target genes.

Results: Our analyses revealed that characteristic disruptions of chromosome 14 are frequently unbalanced. In the commonly deleted region on chromosome 11, we found recurrent microdeletions targeting the microRNA 34b/c and the transcription factors ETS1 and FLI1. On chromosome 8, we identified genes such as PLEKHA2, NBS1, NOV and MYST3 to be involved in breakpoints. New recurrent alterations were identified on chromosomes 5p, 12p, 13q, 17 and 22 with a common region of acquired uniparental disomy in four samples on chromosome 17q. Single nucleotide polymorphism array results were confirmed by direct sequencing and quantitative real-time polymerase chain reaction.

Conclusions: The first high density single nucleotide polymorphism array allelokaryotyping of T-cell prolymphocytic leukemia genomes added substantial new details about established alterations in this disease and moreover identified numerous new potential target genes in common breakpoints, deletions and regions of acquired uniparental disomy.

Key words: T-cell prolymphocytic leukemia, SNP array, uniparental disomy, copy number change.

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