Published online 14 January 2009
Haematologica, Vol 94, Issue 2, 213-223 doi:10.3324/haematol.13024
Copyright © 2009 by Ferrata Storti Foundation

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Acute Myeloid Leukemia

Frequent genomic abnormalities in acute myeloid leukemia/myelodysplastic syndrome with normal karyotype

Tadayuki Akagi^1,#, Seishi Ogawa^2,3,4, Martin Dugas⁵, Norihiko Kawamata¹, Go Yamamoto², Yasuhito Nannya², Masashi Sanada^3,4, Carl W. Miller¹, Amanda Yung¹, Susanne Schnittger⁶, Torsten Haferlach⁶, Claudia Haferlach⁶, H. Phillip Koeffler¹

¹ Division of Hematology and Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA
² Department of Hematology and Oncology and
³ Department of Cell Therapy and Transplantation Medicine and the 21st Century COE Program, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
⁴ Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, Japan
⁵ Department of Medical Informatics and Biomathematics, University of Munster, Munster, Germany
⁶ MLL Munich Leukemia Laboratory, Munich, Germany

Correspondence: Tadayuki Akagi, Ph.D, Division of Hematology and Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine 8700 Beverly Blvd, Los Angeles, CA90048, USA. E-mail:tadayuki{at}staff.kanazawa-u.ac.jp

Background: Acute myeloid leukemia is a clonal hematopoietic malignant disease; about 45–50% of cases do not have detectable chromosomal abnormalities. Here, we identified hidden genomic alterations and novel disease-related regions in normal karyotype acute myeloid leukemia/myelodysplastic syndrome samples.

Design and Methods: Thirty-eight normal karyotype acute myeloid leukemia/myelodysplastic syndrome samples were analyzed with high-density single-nucleotide polymorphism microarray using a new algorithm: allele-specific copy-number analysis using anonymous references (AsCNAR). Expression of mRNA in these samples was determined by mRNA microarray analysis.

Results: Eighteen samples (49%) showed either one or more genomic abnormalities including duplication, deletion and copy-number neutral loss of heterozygosity. Importantly, 12 patients (32%) had copy-number neutral loss of heterozygosity, causing duplication of either mutant FLT3 (2 cases), JAK2 (1 case) or AML1/RUNX1 (1 case); and each had loss of the normal allele. Nine patients (24%) had small copy-number changes (< 10 Mb) including deletions of NF1, ETV6/TEL, CDKN2A and CDKN2B. Interestingly, mRNA microarray analysis showed a relationship between chromosomal changes and mRNA expression levels: loss or gain of chromosomes led, respectively, to either a decrease or increase of mRNA expression of genes in the region.

Conclusions: This study suggests that at least one half of cases of normal karyotype acute myeloid leukemia/myelodysplastic syndrome have readily identifiable genomic abnormalities, as found by our analysis; the high frequency of copy-number neutral loss of heterozygosity is especially notable.

Key words: normal karyotype acute myeloid leukemia/myelodysplastic syndrome, SNP-chip, CNN-LOH.

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				T. Akagi, L.-Y. Shih, S. Ogawa, J. Gerss, S. R. Moore, R. Schreck, N. Kawamata, D.-C. Liang, M. Sanada, Y. Nannya, et al. Single nucleotide polymorphism genomic arrays analysis of t(8;21) acute myeloid leukemia cells Haematologica, September 1, 2009; 94(9): 1301 - 1306. [Abstract] [Full Text] [PDF]