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Mutations of ASXL1 gene in myeloproliferative neoplasms

Leukemia volume 23, pages 2183–2186 (2009)Cite this article

Leukemogenesis is a complex process resulting from the alterations of many genes that perturb the processes leading from a hematopoietic stem cell to a differentiated blood cell. The ASXL1 (additional sex combs like 1) gene is located in the chromosomal region 20q11 and may be affected in hematologic malignancies.1 ASXL1 belongs to a family of three identified members that encode poorly characterized proteins regulating chromatin remodeling. The ASXL proteins contain a C-terminal PHD (plant homeodomain) finger and belong to polycomb and mixed lineage leukemia/trithorax chromatin modifier complexes. We have recently shown that ASXL1 is mutated in roughly 10% of myelodysplastic syndromes (MDS) and 40% of chronic myelomonocytic leukemias;2 mutations were mostly heterozygous, frameshifts, and located in exon 12. The predicted truncated protein would lack its PHD domain, thus compromising the function of the associated chromatin modifiers. In contrast, we did not find mutations of ASXL2 in MDSs and chronic myelomonocytic leukemias (N Carbuccia and MJ Mozziconacci, unpublished). By using high resolution array-comparative genomic hybridization, we also detected a heterozygous loss of ASXL1 in one MDS case.2 These observations suggest that ASXL1 haploinsufficiency plays a role in leukemogenesis.

To determine whether ASXL1 could be involved in other types of myeloid diseases, we studied the ASXL1 gene in 64 myeloproliferative neoplasms (MPNs). Our series comprised 10 cases of polycythemia vera, 35 cases of essential thrombocythemia (ET), 10 cases of primary myelofibrosis (PMF), 1 case of prefibrotic PMF, 5 MPNs at blast phase and 3 unclassifiable MPNs. We also searched for mutations in 12 non-MPN cases comprising 7 secondary thrombocytosis and 5 secondary erythrocytosis. All patients signed an informed consent and the study was approved by our ethical committee. We searched for ASXL1 deletions by array-comparative genomic hybridization on 28 samples by using high-density oligonucleotide microarrays (Hu-244A, Agilent Technologies, Massy, France), as previously described.3 ASXL1 mutations were searched by DNA sequencing, as described.2 We also searched for mutations of JAK2 (V617F) and TET2 (all exons). TET2 mutations have been found in 5–20% of MPN4, 5 and in other myeloid diseases,6, 7, 8 and may be predicted to affect gene regulation.9 TET2 missense mutations were considered when located in conserved regions, spanning amino acids 1134–1444 and 1842–1921.4

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Acknowledgements

This work was supported by Inserm, Institut Paoli-Calmettes and a grant from Association pour la Recherche contre le Cancer (AM, no 4929, 2008).

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Author notes

  1. N Carbuccia, A Murati and V Trouplin: These authors contributed equally to this work.

Authors and Affiliations

  1. Centre de Recherche en Cancérologie de Marseille, Laboratoire d'Oncologie Moléculaire, UMR891 Inserm, Institut Paoli-Calmettes, Marseille, France

    N Carbuccia, A Murati, V Trouplin, M Brecqueville, J Adélaïde, M Chaffanet, D Birnbaum & M J Mozziconacci

  2. Département de BioPathologie, Institut Paoli-Calmettes, Marseille, France

    A Murati & M J Mozziconacci

  3. Département d'Hématologie, Institut Paoli-Calmettes, Marseille, France

    J Rey & N Vey

  4. U790 Inserm, Université Paris XI, Institut Gustave Roussy, Villejuif, France

    W Vainchenker

  5. E0210 Inserm, Hôpital Necker, Paris, France

    O A Bernard

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  1. N Carbuccia
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Correspondence to M J Mozziconacci.

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Carbuccia, N., Murati, A., Trouplin, V. et al. Mutations of ASXL1 gene in myeloproliferative neoplasms. Leukemia 23, 2183–2186 (2009). https://doi.org/10.1038/leu.2009.141

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