Progenitor genotyping reveals a complex clonal architecture in a subset of CALR-mutated myeloproliferative neoplasms.
Br J Haematol
; 177(1): 55-66, 2017 04.
Article
em En
| MEDLINE
| ID: mdl-28168700
ABSTRACT
The identification of acquired CALR mutations in patients with essential thrombocythaemia (ET) or myelofibrosis (MF) has meant that disease-initiating mutations can now be detected in about 90% of all patients with a myeloproliferative neoplasm (MPN). Here, we show that only those CALR mutations that cause a +1 frameshift, thereby altering the carboxy-terminus of calreticulin, promote cytokine independence in vitro; in-frame deletions were not functional, and are unlikely to be the pathogenetic mutation underlying some MPN cases. Expression of the thrombopoietin receptor, MPL, was also necessary for factor-independence. Although the CALR mutations are considered to occur only in JAK2 V617F-negative cases and in a heterozygous state, progenitor genotyping revealed that this is not always true. Notably, CALR mutation-positive MPNs can be polyclonal in one case, two distinct CALR mutation-positive subpopulations could be identified; in another, separate populations of JAK2 V617F-positive and CALR-mutated cells were present. Mitotic recombination involving chromosome 19 in a third instance resulted in the emergence of a CALR mutation-homozygous subclone. Collectively, our studies demonstrate that occasional patients with CALR mutation-positive ET or MF carry other MPN-initiating genetic mutations (including JAK2 V617F), acquire "secondary mutations" before or after the CALR mutation, or evolve over time to being CALR mutation-homozygous.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Células-Tronco Hematopoéticas
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Heterogeneidade Genética
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Calreticulina
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Evolução Clonal
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Genótipo
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Mutação
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Transtornos Mieloproliferativos
Tipo de estudo:
Diagnostic_studies
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Prognostic_studies
Limite:
Animals
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Br J Haematol
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Austrália