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Deletion of the tumor-suppressor gene NF1 occurs in 5% of myeloid malignancies and is accompanied by a mutation in the remaining allele in half of the cases

Leukemia volume 26, pages 834–839 (2012)Cite this article

Myeloid malignancies are characterized by genetic alterations either on the cytogenetic level and/or on the molecular genetic level. A large spectrum of chromosome aberrations and molecular mutations has been identified. These genetic abnormalities lead to alterations of pathways involved in cell proliferation, differentiation and apoptosis. Alterations of the RAS pathway have an important role in the pathogenesis of myeloid malignancies and occur either by activating mutations in RAS itself or by mutations in genes involved in the RAS-dependent pathways, such as FLT3, KIT or CBL. The NF1 gene encodes neurofibromin 1, a Ras-specific guanosine triphosphatase-activating protein that negatively regulates the p21ras (Ras) family of signaling proteins by accelerating GTP hydrolysis to inactive Ras-guanosine diphosphate. Therefore, as NF1 is a negative regulator of RAS signaling, loss of NF1 function is likely to be functionally equivalent to an activating RAS gene mutation. Germline loss-of-function mutations of NF1 lead to neurofibromatosis type I. Carriers of the mutations develop benign neurofibromas and are predisposed not only to neuronal tumors but also to juvenile myelomonocytic leukemia, myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). In addition, in children suffering from chronic myelomonocytic leukemia (CMML) without germline NF1 mutations, acquired loss-of-function mutations of NF1 have been reported. The role of NF1 in adult myeloid malignancies has not been studied in detail so far. Recently, we identified cytogenetically cryptic 17q11 deletions encompassing the NF1 gene in 6 out of 37 AML cases with inv(16)(p13q22)/ t(16;16)(p13;q22).1 17q11.2 deletions including the NF1 gene have also been detected by array comparative genomic hybridization (CGH) in 6 out of 100 consecutive de novo AML cases, 4 showing a complex aberrant karyotype and 2 an inv(16).2 In a study by Rücker et al.,3 in 18 out of 60 AML with complex aberrant karyotype a commonly deleted region on 17p11–17q11 between 23.1 and 29.5 Mb including the NF1 gene was identified by using array CGH. However, only few cases and only a limited number of exons have been investigated for NF1 mutations so far.

In addition to direct repression of transcription, a low NF1 expression could be due to a deletion of one NF1 gene copy. Therefore, we performed fluorescence in situ hybridization (FISH) analysis using a 420-kb probe spanning the NF1 gene (Kreatech, Amsterdam, The Netherlands) in 54/68 of cases with low NF1 expression with material available for FISH analysis. Remarkably, in 11/54 of these cases (20.4%) a NF1 deletion was identified by interphase FISH. This FISH assay detects only complete loss of the NF1 gene and is not able to identify small intragenic deletions. The median proportion of cells with NF1 deletion in individual cases was 90%, ranging from 60 to 99%. In the NF1 low expression group, the mean NF1 expression intensity in cases with NF1 deletion was lower as compared with that of cases with two NF1 copies (60.4 (s.d. ±17.7) vs 75.5 (s.d. ±18.0); P=0.023). Chromosome banding analysis in the 11 cases with NF1 deletion revealed a complex karyotype (n=7, one of these cases with inv(3)(q21q26)), a normal karyotype (n=2), an inv(3)(q21q26) (n=1) and a 5q deletion accompanied by trisomy 21 (n=1), respectively. Details on patients with NF1 deletion are depicted in Table 1.

Table 1 Characteristics of patients with low NF1 expression and NF1 deletion from cohort 1, and of patients with NF1 deletion from cohort 2
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Acknowledgements

We thank all clinicians for sending samples to our laboratory for diagnostic purposes, and for providing clinical information and follow-up data. In addition, we would like to 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, Kathrin Stadler, Marita Staller and Melanie Zenger who performed FISH analyses is greatly appreciated. In addition, we are grateful for the data management support performed by Tamara Alpermann.

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  1. MLL Munich Leukemia Laboratory, Munich, Germany

    C Haferlach, V Grossmann, A Kohlmann, S Schindela, W Kern, S Schnittger & T Haferlach

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  1. C Haferlach
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  2. V Grossmann
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  3. A Kohlmann
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Correspondence to C Haferlach.

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

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Haferlach, C., Grossmann, V., Kohlmann, A. et al. Deletion of the tumor-suppressor gene NF1 occurs in 5% of myeloid malignancies and is accompanied by a mutation in the remaining allele in half of the cases. Leukemia 26, 834–839 (2012). https://doi.org/10.1038/leu.2011.296

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