Transcription factor mutations in myelodysplastic/myeloproliferative neoplasms
Transcription factor mutations in myelodysplastic/myeloproliferative neoplasms
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
1473-1480
Ernst, Thomas
96c7805b-c900-4545-9f93-1a83d789cb56
Chase, Andrew
a40a09c2-3073-4655-ba0b-a802e34914b5
Zoi, Katerina
0bcb986d-3fef-49dc-b9f8-18daf79e8bfb
Waghorn, Katherine
60a6a26d-556b-41fc-84ee-dab95d63ab68
Hidalgo-Curtis, Claire
5aaa8cfa-7271-48ee-8538-27736ab3eaf2
Score, Joannah
ea0db6ef-c17e-4915-b216-ac67c07b26b7
Jones, Amy
3e75587f-611d-47f3-aa52-e4948b368e3a
Grand, Frances
82d7b3a2-9b3c-42ec-aa66-b6b0c69770d6
Reiter, Andreas
ffa23e84-4a13-4cb5-aaf0-3fafe25dbede
Hochhaus, Andreas
b37b9b7d-85ff-455e-994d-fcc2adf94088
Cross, Nicholas C. P.
f87650da-b908-4a34-b31b-d62c5f186fe4
September 2010
Ernst, Thomas
96c7805b-c900-4545-9f93-1a83d789cb56
Chase, Andrew
a40a09c2-3073-4655-ba0b-a802e34914b5
Zoi, Katerina
0bcb986d-3fef-49dc-b9f8-18daf79e8bfb
Waghorn, Katherine
60a6a26d-556b-41fc-84ee-dab95d63ab68
Hidalgo-Curtis, Claire
5aaa8cfa-7271-48ee-8538-27736ab3eaf2
Score, Joannah
ea0db6ef-c17e-4915-b216-ac67c07b26b7
Jones, Amy
3e75587f-611d-47f3-aa52-e4948b368e3a
Grand, Frances
82d7b3a2-9b3c-42ec-aa66-b6b0c69770d6
Reiter, Andreas
ffa23e84-4a13-4cb5-aaf0-3fafe25dbede
Hochhaus, Andreas
b37b9b7d-85ff-455e-994d-fcc2adf94088
Cross, Nicholas C. P.
f87650da-b908-4a34-b31b-d62c5f186fe4
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), .
(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
This record has no associated files available for download.
More information
Accepted/In Press date: 26 April 2010
Published date: September 2010
Identifiers
Local EPrints ID: 148883
URI: http://eprints.soton.ac.uk/id/eprint/148883
ISSN: 0390-6078
PURE UUID: 1582740c-ba5f-406d-bd39-5562b1b4ccc7
Catalogue record
Date deposited: 29 Apr 2010 08:57
Last modified: 14 Mar 2024 02:46
Export record
Altmetrics
Contributors
Author:
Thomas Ernst
Author:
Katerina Zoi
Author:
Katherine Waghorn
Author:
Claire Hidalgo-Curtis
Author:
Joannah Score
Author:
Amy Jones
Author:
Frances Grand
Author:
Andreas Reiter
Author:
Andreas Hochhaus
Download statistics
Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.
View more statistics