Leukemia-associated NF1 inactivation in patients with pediatric T-ALL and AML lacking evidence for neurofibromatosis

Abstract

Blood (print ISSN 0006-4971, online ISSN 1528-0020) IntroductionNeurofibromatosis type 1 (NF1) is an autosomal genetic disorder that is clinically characterized by cafe-au-lait spots and frequent fibromatous tumors of the skin and tumors of the central nervous system. The NF1 disorder is caused by genetic heterozygous mutations in the NF1 gene on chromosome 17q11.2. Most NF1 mutations are intragenic and have been found over the complete gene. They comprise a diversity of mutation types, where splicing mutations are particularly prevalent given the number of exons. This results in truncation for a large percentage of patients, thereby inactivating the encoded protein neurofibromin. 1 Another genetic aberration includes microdeletions affecting the entire NF1 locus. Patients with these NF1 microdeletions display a more severe NF1 phenotype, characterized by mental retardation, facial dysmorphism, and increased risk for developing malignant tumors, including leukemias. 2,3 To this end, NF1 has also been associated with juvenile myelomonocytic leukemia (JMML), with a risk of progression toward acute myeloid leukemia (AML). These malignancies are associated with loss of the wild-type allele, either through deletions or the acquisition of point mutations. In JMML, it has also frequently been reported that the wild-type allele is replaced by the mutant allele as an effect of recombinational events leading to uniparental disomy (UPD). [4][5][6] Previously, it was shown that biallelic inactivation of NF1 are found as somatic abnormalities in patients with JMML who lack clinical evidence of NF1. 7 Somatic inactivation of Nf1 in hematopoietic cells results in a progressive myeloproliferative disorder in mice, 8 confirming that NF1 acts as a tumor-suppressor gene. 5 The NF1 gene protein product, neurofibromin, is a GTPase-activating protein (GAP) that inhibits RAS signaling by hydrolysis of active RAS-GTP into inactive RAS-GDP. 1,9 Therefore, NF1 deficiencies act as functional equivalents of activational mutations in RAS. Indeed, NF1 inactivation and RAS mutations have been found in a mutually exclusive manner in JMML. 7 AML is a heterogeneous disease in which early treatment response and cytogenetic abnormalities are the most important prognostic factors. In AML, genetic aberrations can be classified as type I or type II mutations. One hypothesis about the development of AML is the coexistence of both type I and type II mutations that confer proliferative signals (type I mutations affecting the FLT3, C-KIT, NRAS, KRAS, or PTPN11 genes) in combination with type II differentiation-impairing mutations (such as PML-RAR␣, . 10 MLL-rearrangements account for 8% to 20% of all cytogenetic abnormalities in pediatric AML. 11,12 HOX genes are the prime targets of MLL fusion products and regulate cellular differentiation in normal hematopoietic development. However, Eguchi et al point The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Ther...

Neurofibromatosis‐1 gene deletions and mutations in de novo adult acute myeloid leukemia

“…First, we performed high-resolution array-CGH to better characterize 17q11 somatic losses, allowing the identification of six deletions of various lengths with heterogeneous telomeric and centromeric breakpoints. This differs from a prior study in pediatric T-ALL and AML, where five patients show identical 1.2-Mb NF1 microdeletion, similar to the one described in neurofibromatosis [20]. However, our data are consistent with the previous studies reporting somatic heterogeneous 17q11 deletions in adult myeloid malignancies [5,6,9,21].…”

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

“…[89][90][91] Mutations in FLT3 and KIT are rare in MLL-rearranged AML. 88,92 Recently, novel molecular aberrations were found in pediatric AML, that is, mutations in NPM1, CEBPA and WT1. Of these mutations, only WT1 mutations were found in MLL-rearranged AML, and these even at a low frequency.…”

High BRE expression in pediatric MLL-rearranged AML is associated with favorable outcome

“…21 NPM1, CEBPA, WT1, NRAS, KRAS, PTPN11, CKIT and FLT3 hotspot mutational screening was performed as previously described. [22][23][24][25][26] Overexpression of EVI1 was previously established by gene expression profiling and real-time quantitative (RQ)-PCR. 27 Microarray-based gene expression profiling Integrity of total RNA was checked using the Agilent 2100 Bioanalyzer (Agilent, Santa Clara, CA, USA).…”