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SETBP1 mutations in 658 patients with myelodysplastic syndromes, chronic myelomonocytic leukemia and secondary acute myeloid leukemias

Leukemia volume 27, pages 1401–1403 (2013)Cite this article

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Massively parallel sequencing technology has recently identified recurrent somatic mutations in SETBP1 gene in atypical chronic myeloid leukemia.1 SETBP1 is located on chromosome 18q21.1 and encodes SET binding protein 1. Identical nucleotide alterations resulting in protein changes affecting predominantly residues 858–871 have been reported in Schinzel-Giedion syndrome, a rare congenital disorder, characterized by severe mental retardation, distinctive facial features and multiple congenital malformations.2 The mutations target the substrate recognition domain of the E3 ubiquitin ligase and may affect ubiquitin binding1 A functional impact of SETBP1 mutations is highly likely as cell lines transfected with mutated SETBP1 exhibit increased SETBP1 protein levels, enhanced inhibition of PP2A activity and higher proliferation rates.1 SETBP1 has been identified as a rare chromosomal translocation partner in lymphoid and myeloid acute leukemias.3, 4 Its overexpression, which is associated also with aberrations of chromosome 7 and poor prognosis in acute myeloid leukemias (AML),4 was shown to confer self-renewal capabilities to murine myeloid progenitors.5

To date, little is known regarding prevalence, clinical and prognostic value of SETBP1 mutations in other myeloid malignancies. We therefore investigated the mutational hotspot of SETBP1 in a large cohort of 195 chronic myelomonocytic leukemia (CMML), 222 myelodysplastic syndromes (MDS) and 241 secondary AML (sAML) patients by Sanger sequencing. CMML and MDS patient samples were collected in noninterventional studies (MYELOMONO and MAD-06, respectively) by the Groupe Francophone des Myelodysplasies (GFM), and sAML patient samples were collected at enrollment in multicenter clinical trials by the Groupe Ouest-Est d’étude des Leucémies Aiguës et Autres Maladies du Sang (GOELAMS). Informed consent was obtained from all patients in accordance with the Declaration of Helsinki. Both GFM and GOELAMS studies were approved by the Paris Center ethics committee. For all three cohorts, patient characteristics and treatment details have been published earlier.6, 7, 8

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Acknowledgements

We thank the investigators of the Groupe Francophone des Myélodysplasies and Groupe Ouest-Est d’étude des Leucémies Aiguës et Autres Maladies du Sang for including patients, and M Bourmaud for technical assistance. This study was supported by grant no. 109686 from the Deutsche Krebshilfe awarded to FD and grants from the Program Hospitalier de Recherche Clinique (MDS-04 to MF and MYELOMONO to ES), Association Laurette Fugain (to ND), Ligue Nationale Contre le Cancer (to OAB and to ES) and INCa translational research grants (to MF, and to ES).

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Author notes

  1. F Damm and R Itzykson: These authors contributed equally to this work.

Authors and Affiliations

  1. Institut Gustave Roussy, Villejuif, France

    F Damm, R Itzykson, N Droin, S de Botton, O A Bernard & E Solary

  2. Université Paris-Sud, Orsay, France

    F Damm, R Itzykson, N Droin, S de Botton, O A Bernard & E Solary

  3. INSERM, U985, Villejuif, France

    F Damm, S de Botton & O A Bernard

  4. INSERM U1009, Villejuif, France

    R Itzykson, N Droin & E Solary

  5. Département d’Immunologie et Hématologie, Institut Cochin, Paris, France

    O Kosmider, V Chesnais & M Fontenay

  6. Université Paris Descartes, Paris, France

    O Kosmider, V Chesnais & M Fontenay

  7. Assistance Publique-Hôpitaux de Paris, Service d’Hématologie Biologique, Broca-Cochin-Hôtel-Dieu, Paris, France

    O Kosmider, V Chesnais & M Fontenay

  8. Laboratory of Hematology, Biology and Pathology Center, CHRU of Lille, Lille, France

    A Renneville & C Preudhomme

  9. Institut Paoli-Calmette, Marseille, France

    V Gelsi-Boyer, N Vey, D Birnbaum & E Solary

  10. INSERM U1068, Centre de Recherche en Cancérologie de Marseille, Marseille, France

    V Gelsi-Boyer & D Birnbaum

  11. Université d’Aix-Marseille, Marseille, France

    V Gelsi-Boyer, N Vey & D Birnbaum

  12. Service d’Hématologie, Institut Gustave Roussy, Villejuif, France

    S de Botton

  13. Département d’Hématologie, Institut Paoli-Calmettes, Marseille, France

    N Vey

  14. University of Lille Nord de France, Lille, France

    C Preudhomme

  15. INSERM, U837, Cancer Research Institute of Lille, Lille, France

    C Preudhomme

  16. Service d’Hématologie Clinique, CHU, Angers, France

    A Clavert

  17. Laboratoire d’Hematologie, CHU Purpan, Toulouse, France

    E Delabesse

  18. Unité Fonctionnelle d’hématologie clinique, Hôpital Cochin, Paris, France

    S Park

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  1. F Damm
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  2. R Itzykson
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  16. O A Bernard
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Correspondence to E Solary.

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Damm, F., Itzykson, R., Kosmider, O. et al. SETBP1 mutations in 658 patients with myelodysplastic syndromes, chronic myelomonocytic leukemia and secondary acute myeloid leukemias. Leukemia 27, 1401–1403 (2013). https://doi.org/10.1038/leu.2013.35

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