Research Article: Identification of Novel Genomic Aberrations in AML-M5 in a Level of Array CGH

Date Published: April 11, 2014

Publisher: Public Library of Science

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


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.

Partial Text

Acute monocytic leukemia, also named acute myeloid leukemia-M5 (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). Responses to chemotherapy and prognosis in AML-M5 patients are varied. The recently proposed World Health Organization (WHO) classification attempts to associate the prognostic variance with cytogenetic abnormalities [1]–[2]. However, rather than t(8;21) in AML-M2, t(15;17) in AML-M3 and inv(16)/t(16;16) in AML-M4eo, specific subtype-associated translocation is lacking in AML-M5. 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. Especially those cryptic alterations, which are invisible for traditional banding analysis, are not rare in AML with normal karyotype [5]–[6].

In the last few years, the classification of AML has developed from a single morphological level to a MICM basis. As one of the diagnostic methods, genetic abnormality examination plays an important role in further sub-classification of AML and gives more clues to therapy selection and prognosis [1]–[2]. The cohort of patients of our study is in a special subgroup of AML, AML-M5, which is characterized by variable therapy responses and low incidence of recurrent chromosomal abnormalities at the level of conventional cytogenetic method. The present study refined the genomic aberrations of AML-M5 by an integration of chromosome, FISH and array CGH procedure. The majority of the genomic alterations are cryptic and invisible to G-banding analysis, indicating that high-resolution array CGH approach is necessary to provide more precise description of chromosomal aberrations in AML-M5. Particularly, in the patients with normal karyotype, array CGH has been able to unveil the small CNAs. However, similar with the previous studies, the recurrence of the small CNAs is very low [19]–[20]. Normal genomes are observed in nearly half of the AML-M5s, inferring that additional studies, such as gene sequencing or epigenetic analysis, might be necessary to investigate the underlying mechanism of AML-M5.