Transcription factor mutations in myelodysplastic/myeloproliferative neoplasms

Ernst, Thomas, Chase, Andrew, Zoi, Katerina, Waghorn, Katherine, Hidalgo-Curtis, Claire, Score, Joannah, Jones, Amy, Grand, Frances, Reiter, Andreas, Hochhaus, Andreas and Cross, Nicholas C. P. (2010) Transcription factor mutations in myelodysplastic/myeloproliferative neoplasms. Haematologica, 95 (9), 1473-1480. (doi:10.3324/haematol.2010.021808).

Abstract

Background: aberrant activation of tyrosine kinases, caused either by mutation or gene fusion, is of major importance for the development of many hematological malignancies, particularly myeloproliferative neoplasms (MPN). We hypothesized that hitherto unrecognized, cytogenetically cryptic tyrosine kinase fusions may be common in non-classical or atypical MPN and related myelodysplastic/myeloproliferative neoplasms (MDS/MPN).

Design and Methods: to 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 hybridisation (CGH). 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.

Results: no 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, respectively. A further mutation screen of 187 MDS/MPN patients 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%) MDS/MPN patients, respectively. Univariate analysis indicated that patients with mutations had a shorter
overall survival (28 vs. 44 months, P=0.019) compared with mutation negative cases, with the prognosis for cases with CEBPA, NPM1 or WT1 mutations being particularly poor.

Conclusions: we conclude that mutations of transcription and other nuclear factors are frequent in MDS/MPN 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

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Contributors

Author: Andrew Chase

Author: Nicholas C. P. Cross

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