Identification of novel genomic aberrations in AML-M5 in a level of array CGH.

Rui Zhang,Weihong Xu,Xianfu Wang,Xianglan Lu,Shibo Li,Ji-Yun Lee,Yan Li,Yimeng Niu,Rurong Tang,Xiaoxia Hu,Javier S Castresana

doi:10.1371/journal.pone.0087637

Abstract

To assess the possible existence of unbalanced chromosomal abnormalities and delineate the characterization of copy number alterations (CNAs) of acute myeloid leukemia-M5 (AML-M5), R-banding karyotype, oligonucelotide array CGH and FISH were performed in 24 patients with AML-M5. A total of 117 CNAs with size ranging from 0.004 to 146.263 Mb was recognized in 12 of 24 cases, involving all chromosomes other than chromosome 1, 4, X and Y. Cryptic CNAs with size less than 5 Mb accounted for 59.8% of all the CNAs. 12 recurrent chromosomal alterations were mapped. Seven out of them were described in the previous AML studies and five were new candidate AML-M5 associated CNAs, including gains of 3q26.2-qter and 13q31.3 as well as losses of 2q24.2, 8p12 and 14q32. Amplication of 3q26.2-qter was the sole large recurrent chromosomal anomaly and the pathogenic mechanism in AML-M5 was possibly different from the classical recurrent 3q21q26 abnormality in AML. As a tumor suppressor gene, FOXN3, was singled out from the small recurrent CNA of 14q32, however, it is proved that deletion of FOXN3 is a common marker of myeloid leukemia rather than a specific marker for AML-M5 subtype. Moreover, the concurrent amplication of MLL and deletion of CDKN2A were noted and it might be associated with AML-M5. The number of CNA did not show a significant association with clinico-biological parameters and CR number of the 22 patients received chemotherapy. This study provided the evidence that array CGH served as a complementary platform for routine cytogenetic analysis to identify those cryptic alterations in the patients with AML-M5. As a subtype of AML, AML-M5 carries both common recurrent CNAs and unique CNAs, which may harbor novel oncogenes or tumor suppressor genes. Clarifying the role of these genes will contribute to the understanding of leukemogenic network of AML-M5.

Highlights

Named acute myeloid leukemiaM5 (AML-M5), is one of the most common subtypes of AML defined by the French-American-British (FAB), which is comprised by more than 80% of monoblasts (AML-M5a) or 30–80% monoblasts withmonocytic differentiation (AML-M5b)
File S1). 11 of them (10 newly diagnosed cases and 1 relapsed case) had normal karyotypes and 5 cases carried 2 or 3 chromosomal abnormalities. t(9;11)(p22;q23) as the recurrent chromosomal change was presented in 3 cases
In contrast to the most common recurrent copy number alterations (CNAs) reported by 8 representative genomic studies of MDS and AML using oligonucleotide array CGH or SNP array [5,12,13,14,15,16,17,18] (Table 2), novel CNAs including gains of 3q26.2-qter and 13q31.3 as well as losses of 2q24.2, 8p12 and 14q32 were proposed in the present study

Summary

Introduction

Named acute myeloid leukemiaM5 (AML-M5), is one of the most common subtypes of AML defined by the French-American-British (FAB), which is comprised by more than 80% of monoblasts (AML-M5a) or 30–80% monoblasts with (pro)monocytic differentiation (AML-M5b). It has been described that a part of AML-M5 patients carry 11q23 (MLL gene) rearrangement with a wide spectrum of recurrent translocation partner chromosomes [3,4]. In this sense, it is reasonable to assume that unbalanced chromosomal abnormalities might play a major role in the leukemogenesis of AML-M5. It is reasonable to assume that unbalanced chromosomal abnormalities might play a major role in the leukemogenesis of AML-M5 Those cryptic alterations, which are invisible for traditional banding analysis, are not rare in AML with normal karyotype [5,6]

Methods

Results

Conclusion