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AML with CBFB–MYH11 rearrangement demonstrate RAS pathway alterations in 92% of all cases including a high frequency of NF1 deletions

Leukemia volume 24, pages 1065–1069 (2010)Cite this article

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Acute myeloid leukemia (AML) with abnormal bone marrow eosinophils and with inv(16)(p13q22) or t(16;16)(p13;q22) leading to a CBFB–MYH11 fusion gene have been defined as a distinct entity by the World Health Organization classification and are associated with a favorable outcome. The CBFB–MYH11 fusion proteins are interfering in a dominant-negative manner with core binding factor (CBF), thereby impairing hematopoietic differentiation and predisposing cells to leukemic transformation. However, knock-in mouse models have demonstrated that CBFB–MYH11 alone is not sufficient to cause a leukemic phenotype and that additional aberrations were essential for the development of AML.1 Secondary cytogenetic abnormalities occur in ∼40% of cases with +22, +8 (10–15% each), and del(7q) or +21 is most commonly observed. Recent molecular analyses have also provided important insights into the pathogenesis of myeloid disorders, and the commonly detected mutations of KIT and NRAS genes as well as deregulated CEBPA expression have been identified as likely candidates for cooperating events in CBF-positive AML.2, 3 Recently, exon 8 splice site mutations in the gene encoding the E3-ligase CBL have been reported in three cases with inv(16), suggesting an alternative mechanism of activating tyrosine kinases, as mutant CBL may act as a dominant-negative protein by inhibiting proper downregulation of activated tyrosine kinases, such as KIT and FLT3.4

This study was performed to further decipher accompanying genetic lesions at the molecular level in AML with CBFB–MYH11 rearrangements. Therefore, chromosome banding analyses, single-nucleotide polymorphism (SNP) array analyses and comprehensive screening for mutations in the genes KIT, NRAS, KRAS, FLT3, CBL, PTPN11 and JAK2 were performed in 37 newly diagnosed AML with CBFB–MYH11 rearrangement. Details on patient's characteristics are provided in the Supplementary Information. Patients gave their informed consent for this investigation. The study abides by the rules of the local Internal Review Board and the tenets of the revised Helsinki protocol. Chromosome banding analysis was available in all cases. In total, 30 cases showed an inv(16)(p13q22), whereas in 5 cases a t(16;16)(p13;q22) was observed. Two patients showed a normal karyotype with a cryptic CBFB–MYH11 rearrangement confirmed by reverse transcriptase PCR. Using standard chromosome banding analysis, additional cytogenetic aberrations were observed in 13 cases with de novo AML and in 1 case with t(therapy-related)-AML (37.8%). Karyotypes of patients with additional chromosome aberrations are depicted in the Supplementary Information (Supplementary Table S1). Recurring additional aberrations were +22 (n=6), +8 (n=5) or +8q (n=1), +13 (n=1) or +13q (n=1), −Y (n=2) and del(7q) (n=2). Gains and losses as well as large regions of copy-neutral loss of heterozygosity detected by SNP array analysis are depicted in detail in Table 1. Detailed information on chromosomal gains and losses identified by SNP arrays as compared with chromosome banding analysis are provided in the Supplementary Information. A 7q deletion was observed in a total of four cases. Two of these were detected by SNP array analyses only; they were missed by cytogenetics because of their small size. On the basis of SNP array data, the commonly deleted region was identified to range from 7q36.1 to 7q36.3 (size: 8.5 Mb; physical map position 147 549 804–156 038 680). In addition to a gain of the whole chromosome 8, which was frequently observed as an additional aberration, SNP array analyses revealed only a partial gain on 8q in one case, which was missed by cytogenetics because of the small size ranging from 8q24.13 to 8q24.3 (size: 25.3 Mb; physical map position 120 986 982–146 268 936). Furthermore, a recurrent deletion (n=2) on chromosome 18 was detected by SNP array, but not detected by cytogenetics. The commonly deleted region was localized in 18q23 (size: 3.1 Mb; physical map position 72 481 657–75 604 994). Most interestingly, in six cases a small deletion ranging from 0.46 to 2.18 Mb on 17q11 not visible by chromosome banding analysis was identified by SNP array analysis. The only gene included in the minimal deleted region was the NF1 gene. In two cases, the CBFB–MYH11 rearrangement was cryptic and could not be detected by chromosome banding analysis or fluorescent in situ hybridization (FISH) using two probes flanking the breakpoints within the CBFB gene. However, a CBFB–MYH11 transcript was amplified by reverse transcriptase PCR. In one of these cases, the SNP array data revealed a small gain on 16p13 including the 3′ part of the MYH11 gene (size: 71 kb; physical map position 15 654 558–15 725 636), suggesting the insertion of additional 3′ MYH11 sequences into the CBFB locus leading to the CBFB–MYH11 fusion gene.

Table 1 Results of single-nucleotide polymorphism array analysis
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Acknowledgements

We thank all clinicians for sending AML samples to our laboratory for diagnostic purposes and for providing clinical information and follow-up data. In addition, the authors thank all co-workers at the MLL—Munich Leukemia Laboratory for approaching together many aspects in the field of leukemia diagnostics and research. Especially the technical assistance of Annika Eßer who performed FISH analyses is greatly appreciated.

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  1. MLL Munich Leukemia Laboratory, Munich, Germany

    C Haferlach, F Dicker, A Kohlmann, S Schindela, T Weiss, W Kern, S Schnittger & T Haferlach

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  1. C Haferlach
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Correspondence to C Haferlach.

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CH, WK, SuS and TH are equity owners of the Munich Leukemia Laboratory, and FD, AK, SoS and TW are employed by the Munich Leukemia Laboratory.

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Haferlach, C., Dicker, F., Kohlmann, A. et al. AML with CBFB–MYH11 rearrangement demonstrate RAS pathway alterations in 92% of all cases including a high frequency of NF1 deletions. Leukemia 24, 1065–1069 (2010). https://doi.org/10.1038/leu.2010.22

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