Transcription factor mutations in myelodysplastic/myeloproliferative neoplasms.
BACKGROUND
Aberrant 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.


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 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.


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. 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.


CONCLUSIONS
We 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.
Ernst
Thomas
T
Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury SP2 8BJ, United Kingdom.
Chase
Andrew
A
Zoi
Katerina
K
Waghorn
Katherine
K
Hidalgo-Curtis
Claire
C
Score
Joannah
J
Jones
Amy
A
Grand
Francis
F
Reiter
Andreas
A
Hochhaus
Andreas
A
Cross
Nicholas C P
NC
D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D055028:Comparative Genomic Hybridization; D004252:DNA Mutational Analysis; D018628:Gene Dosage; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D038042:Myelopoiesis / Q000235:genetics; D009196:Myeloproliferative Disorders / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D000090243:Nucleophosmin; D011379:Prognosis; D014157:Transcription Factors / Q000235:genetics*; D025721:WT1 Proteins / Q000235:genetics
D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors; D025721:WT1 Proteins; D000090243:Nucleophosmin