Transcription factor mutations in myelodysplastic/myeloproliferative neoplasms

Abstract

The online version of this article has a Supplementary Appendix. BackgroundAberrant activation of tyrosine kinases, caused by either mutation or gene fusion, is of major importance for the development of many hematologic malignancies, particularly myeloproliferative neoplasms. We hypothesized that hitherto unrecognized, cytogenetically cryptic tyrosine kinase fusions may be common in non-classical or atypical myeloproliferative neoplasms and related myelodysplastic/myeloproliferative neoplasms. Design and MethodsTo detect genomic copy number changes associated with such fusions, we performed a systematic search in 68 patients using custom designed, targeted, high-resolution array comparative genomic hybridization. Arrays contained 44,000 oligonucleotide probes that targeted 500 genes including all 90 tyrosine kinases plus downstream tyrosine kinase signaling components, other translocation targets, transcription factors, and other factors known to be important for myelopoiesis. ResultsNo abnormalities involving tyrosine kinases were detected; however, nine cytogenetically cryptic copy number imbalances were detected in seven patients, including hemizygous deletions of RUNX1 or CEBPA in two cases with atypical chronic myeloid leukemia. Mutation analysis of the remaining alleles revealed non-mutated RUNX1 and a frameshift insertion within CEBPA. A further mutation screen of 187 patients with myelodysplastic/myeloproliferative neoplasms identified RUNX1 mutations in 27 (14%) and CEBPA mutations in seven (4%) patients. Analysis of other transcription factors known to be frequently mutated in acute myeloid leukemia revealed NPM1 mutations in six (3%) and WT1 mutations in two (1%) patients with myelodysplastic/myeloproliferative neoplasms. Univariate analysis indicated that patients with mutations had a shorter overall survival (28 versus 44 months, P=0.019) compared with patients without mutations, with the prognosis for cases with CEBPA, NPM1 or WT1 mutations being particularly poor. ConclusionsWe conclude that mutations of transcription and other nuclear factors are frequent in myelodysplastic/myeloproliferative neoplasms and are generally mutually exclusive. CEBPA, NPM1 or WT1 mutations may be associated with a poor prognosis, an observation that will need to be confirmed by detailed prospective studies. Haematologica 2010;95(9):1473-1480. doi:10.3324/haematol.2010 This is an open-access paper. Transcription factor mutations in myelodysplastic/myeloproliferative neoplasms

World Health Organization Classification, Evaluation, and Genetics of the Myeloproliferative Neoplasm Variants

“…41 However, mutations of CBL, RUNX1, CEBPA, EZH2, and WT1 occur in a similar frequency as in CMML. 31,42 …”

“…38 In contrast, mutations affecting the transcription factors RUNX1, CEBPA, NPM1, or WT1 have been reported in up to 30% of cases of CMML, but to date not in JMML. 31,38 Other mutations overrepresented in CMML, such as mutated JAK2, ASXL1, TET2, and IDH1/2, are also rare in JMML. The significance of these genetic abnormalities on the future classification of CMML or JMML is not clear, but the reported association of RAS mutations with the myeloproliferative features of CMML may provide an objective criterion for further subclassification into myeloproliferative-like and myelodysplastic-like subtypes, an issue addressed in a previous French-American-British (FAB) classification but not in the current WHO system.…”

“…More recently, the application of genetic techniques such as single nucleotide polymorphism arrays and high-throughput sequencing have revealed several genetic abnormalities, including mutations of genes encoding transcription factors such as RUNX1 and CEBPA-abnormalities rarely seen in MPNs-that buttress the argument that the MDS/MPN neoplasms are unique. [29][30][31] There are no currently known cytogenetic or molecular genetic abnormalities specific for any MDS/MPN. The finding of BCR-ABL1 or rearrangements of PDGFRA, PDGFRB, or FGFR1 excludes the diagnosis of MDS/MPN, which are defined largely by their clinical and morphologic findings.…”

“…Cytogenetics: clonal cytogenetic abnormalities in up to 80%; trisomy 8 and del(20q) are the most common, but abnormalities of chromosomes 13,14,17,19, and 12 are also commonly reported. 40 Molecular genetics: mutated NRAS, KRAS, or TET2 in nearly 30% 37 ; mutations of CBL, RUNX1, CEBPA, EZH2, or WT1 in 1%-10% 31,42,55 ; and JAK2 V617F occurs rarely if at all. 40 …”

Genomic profiling and directed ex vivo drug analysis of an unclassifiable myelodysplastic/myeloproliferative neoplasm progressing into acute myeloid leukemia

“…This category also comprises atypical chronic myeloid leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, and refractory anemia with ring sideroblasts and thrombocytosis (Vardiman et al, 2009). Of these, MDS/MPN-U is the least well characterized group and no specific genetic alterations have been found; instead they share many alterations with myeloid disorders, including isolated trisomy 8 and recurrent mutations in, e.g., DNMT3A, JAK2, KRAS/NRAS, RUNX1, and SETBP1 (Ernst et al, 2010;Meggendorfer et al, 2013;DiNardo et al, 2014;Wang et al, 2014). Recently, mutations in ASXL1, TET2, and U2AF1 were shown to occur at high frequencies in MDS/MPN-U, with mutations in U2AF1 being enriched in this subtype (Meggendorfer et al, 2014).…”