RGD Reference Report - Disruption of the ASXL1 gene is frequent in primary, post-essential thrombocytosis and post-polycythemia vera myelofibrosis, but not essential thrombocytosis or polycythemia vera: analysis of molecular genetics and clinical phenotypes. - Rat Genome Database

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Disruption of the ASXL1 gene is frequent in primary, post-essential thrombocytosis and post-polycythemia vera myelofibrosis, but not essential thrombocytosis or polycythemia vera: analysis of molecular genetics and clinical phenotypes.

Authors: Stein, BL  Williams, DM  O'Keefe, C  Rogers, O  Ingersoll, RG  Spivak, JL  Verma, A  Maciejewski, JP  McDevitt, MA  Moliterno, AR 
Citation: Stein BL, etal., Haematologica. 2011 Oct;96(10):1462-9. doi: 10.3324/haematol.2011.045591. Epub 2011 Jun 28.
RGD ID: 11038705
Pubmed: PMID:21712540   (View Abstract at PubMed)
PMCID: PMC3186307   (View Article at PubMed Central)
DOI: DOI:10.3324/haematol.2011.045591   (Journal Full-text)

BACKGROUND: The myeloproliferative neoplasms, essential thrombocytosis, polycythemia vera and primary myelofibrosis, share the same acquired genetic lesion, but the concept of JAK2 V617F serving as the sole lesion responsible for these neoplasms is under question, and there has been interest in identifying additional mutations that may contribute to disease pathogenesis. Because ASXL1 lesions have been increasingly identified in myeloid neoplasms, we examined the relationships of ASXL1 mutation or deletion to both clinical phenotype and associated molecular features in 166 patients with myeloproliferative neoplasms. DESIGN AND METHODS: Exon 12 of ASXL1 was amplified from neutrophil genomic DNA and bidirectionally sequenced in 77 patients with myelofibrosis (including patients with primary and post-essential thrombocytosis or post-polycythemia myelofibrosis), 42 patients with polycythemia vera, 41 with essential thrombocytosis and 6 with post-myelofibrosis acute myeloid leukemia. Pyrosequencing assays were designed to determine the allele percentages of JAK2 V617F (G5073770T), ASXL1 2475dupA, and ASXL1 2846_2847del in neutrophil genomic DNA samples. Clinical and laboratory characteristics of patients with wild-type and ASXL1 mutations were then compared. RESULTS: We identified nonsense mutations or hemizygous deletion of ASXL1 in 36% of the patients with myelofibrosis, but very rarely among those with polycythemia vera or essential thrombocytosis. Among the patients with myelofibrosis, those with ASXL1 lesions were not distinguished from their wild-type counterparts with regard to JAK2 V617F status, exposure to chemotherapy or evolution to leukemia. Myelofibrosis patients with ASXL1 lesions were more likely to have received anemia-directed therapy compared to those without lesions [15/26 (58%) versus 11/39 (23%); P=0.02]. Using serial banked samples and quantitative ASXL1 mutant allele burden assays, we observed the acquisition and accumulation of ASXL1 mutations over time in two patients with post-essential thrombocytosis myelofibrosis. CONCLUSIONS: ASXL1 haploinsufficiency is associated with a myelofibrosis phenotype in the context of other known and unknown lesions, and disruption of ASXL1 function may contribute to the disease pathogenesis of myelofibrosis.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
myelofibrosis  IAGP 11038705DNA:mutation more ...RGD 
myelofibrosis  ISOASXL1 (Homo sapiens)11038705; 11038705DNA:mutation more ...RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Anemia  IAGP 11038705associated with Primary Myelofibrosis more ...RGD 
Objects Annotated

Genes (Rattus norvegicus)
Asxl1  (ASXL transcriptional regulator 1)

Genes (Mus musculus)
Asxl1  (ASXL transcriptional regulator 1)

Genes (Homo sapiens)
ASXL1  (ASXL transcriptional regulator 1)


Additional Information