High-resolution single-nucleotide polymorphism array-profiling in myeloproliferative neoplasms identifies novel genomic aberrations

Abstract

-resolution single-nucleotide polymorphism array-profiling in myeloproliferative neoplasms identifies novel genomic aberrations. Haematologica. 2010;95: 666-669. doi:10.3324/haematol.2009 This is an open-access paper. ABSTRACT © F e r r a t a S t o r t i F o u n d a t i o ngain of 1q (n=4), and trisomy 8 (n=4), followed by loss of 5q11-q13 and 13q12-q21 in single cases (Table 1). While 20q losses occurred in all MPN subgroups, gain of 9p / trisomy 9 was restricted to PV and secondary MF patients, and trisomy 8 to PMF patients. Gain of 1q was observed in one PV, one ET, and 2 PMF cases. In addition, SNP-profiling revealed two recurrent small CNAs that were undetectable in cytogenetic studies: 11 ET and 2 PV patients showed small gains in 10q11.22 (1.5-2.7 Mb), whereas one post-ET and one post-PV MF case exhibited microdeletions in 17q11.2 (1.6 and 2.7 Mb, respectively) encompassing the tumor suppressor gene Neurofibromatosis-1 (NF1).To validate these findings, matched pair analysis using germline and tumor material was performed in a subset of these cases. Skin biopsies were taken from 2 patients with 10q11 gain and from one patient with 17q11 loss. SNPprofiles revealed that 10q11 gains represented CNVs in both cases, whereas the tumor-specific origin of cryptic deletion in 17q11 was confirmed (Figure 1). The disclosure of the 10q11 CNV reduced the frequency of detected CNAs in ET and PV to 11% each. Furthermore, fluorescence in situ hybridization performed in both cases with loss in 17q11 showed monoallelic NF1 deletion in nearly 100% of the metaphase and interphase cells. Mutation analysis revealed a single base pair deletion in exon 5 (c.528delT) leading to a stop codon in the post-PV MF patient, whereas in the post-ET case no sequence variations were detected. With regard to the clinical phenotype in both patients MF was secondary to a prior ET or PV, respectively. Both cases were characterized by a progressive clinical course and both patients underwent allogeneic stem cell transplantation. Of note, the patient with monoallelic NF1 deletion reached a sustained complete remission, whereas the patient with biallelic NF1 alteration transformed into acute myeloid leukemia three months after transplantation and died.NF1 is associated with the hereditary von Recklinghausen's neurofibromatosis. It has been shown that these patients have an increased risk of developing various tumors including myeloid leukemias.5 NF1 functions as a negative regulator of the RAS signal transduction pathway, and loss of NF1 can lead to a progressive myeloproliferative disorder.6 Cases with cryptic deletions in 17q11 encompassing NF1 have been identified in several recent studies on adult and childhood acute myeloid and T-lymphoblastic leukemia patients as well as in PMF patients. [7][8][9][10] In addition, Balgobind et al. identified in 3 out of 4 childhood leukemia patients with monallelic NF1 deletions truncating mutations in the remaining allele, that resulted in biallelic inactivation of the gene.9 Taken together, these data stro...

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

“…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]. Interestingly, we have identified a small MDR of 0.3 Mb, which contains only four genes, NF1, and three genes embedded in intron 27b of NFI (OMG, EVI2B, and EVI2A) (Fig.…”

Inactivation of polycomb repressive complex 2 components in myeloproliferative and myelodysplastic/myeloproliferative neoplasms

“…on May 8, 2018. by guest www.bloodjournal.org From analyzed 2 patients (UPN23 and UPN30) from a previously described cohort of MPN cases (n ϭ 151). 20 The study was approved by the internal review boards of all participating institutions and informed consent was provided according to the Declaration of Helsinki. …”

Molecular basis and clonal evolution of myeloproliferative neoplasms

“…NF1 is a well known negative regulator of RAS, enhancing its intrinsic GTPase activ ity via the hydrolyzation of GTP to GDP. Deletions of the NF1 tumor suppressor gene have been observed in many cohorts of patients, particularly those in chronic phrase, whereas NRAS mutations seem to primarily affect patients that have transformed to AML [38].…”

“…Recent studies have indicated that members of this pathway, such as NF1 and NRAS, are often mutated in MPNs, contributing to the myeloproliferative phenotype [37,38]. Mutations in NRAS seem to result in the consti tutive activation of the protein, thus affecting the expres sion of the JAK2 target genes.…”