Deletion of the Tumor Suppressor Gene NF1 Is Found In 3.5% of 485 De Novo Adult Myeloid Leukemia and Is Correlated with Unfavourable Cytogenetic: On Behalf of the ALFA Group

Abstract

AbstractAbstract 4171NF1 acts as a tumor-suppressor gene by encoding neurofibromin1, a GTPase-activating protein (GAP) inhibiting Ras signaling pathway. Germline mutations or microdeletions of NF1 are responsible for neurofibromatosis type 1, and the somatic loss of the remained wild-type allele lead to malignant tumors or juvenile myelomonocytic leukemia (JMML). Furthermore, several studies revealed heterozygous somatic deletions of the 17q11.2 region including NF1 in adult myeloid malignancies. The reported frequencies of this abnormality varied between 2.6% and 11% in AML and this variation can be attributable to heterogeneity or size of the analysed cohorts.Previously, we analyzed 131 de novo AML cases (AML3 excluded) by Agilent™ 105K microarrays. 6/131 cases (4.6%) showed somatic deletions in 17q11.2, including a small minimal deleted region of 300 kb comprising the entire NF1 gene. To further investigate the incidence of NF1 deletion in de novo AML, 354 additional patients were therefore screened for the deletion by quantitative real-time PCR (Primers and TaqMan-based probe Hs 01778367_cn from Applied Biosystems), and FISH (NF1/MPO probe KBI-40144 from Kreatech) was performed to confirm the loss of NF1 copy number. Altogether, heterozygous NF1 deletion was observed in 17/485 (3.5%) de novo AML. Clinico-biological data were available from 14 NF1 deleted patients and 380 non-deleted patients included in the ALFA-9801 and 9802 French Trials. There were no significant differences between the 2 groups in age, sex ratio, leukocytosis, FAB classification of AML, mutational status of FLT3, NPM1, CEBPα and IDH. Interestingly, NF1 deletion was significantly correlated with unfavourable cytogenetic (50% vs 18%, p=0.008) and especially with monosomal karyotype (29% vs 9%, p=0.03). However, no statistical significant differences were observed for complete remission rate, relapse risk 3 years after diagnosis and 3-years overall survival. Screening for bi-allelic inactivation by sequencing the remained allele in NF1 deleted patients is in progress.We next evaluated NF1 gene expression for 93 patients of our cohort (3 with NF1 deletion and 90 without) by Affymetrix U133 Plus 2.0 microarrays. The 3 NF1 deleted patients revealed a significant reduced mean of NF1 expression level. Interestingly, about 10% of the NF1 non-deleted patients presented a similar decrease in NF1 expression rate. This suggests that mechanisms for transcriptional regulation (such as mutations or epigenetic silencing of NF1) may also contribute to AML pathogenesis.In conclusion, NF1 deletions occur in only 3.5% of de novo AML and are associated with unfavourable cytogenetic. This relatively low frequency of NF1 deletion can however be counterbalanced by others alterations acting at the transcriptional level and this remains to be investigated. Disclosures:No relevant conflicts of interest to declare.