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CHRONIC MYELOPROLIFERATIVE NEOPLASMS

Germline ATG2B/GSKIP-containing 14q32 duplication predisposes to early clonal hematopoiesis leading to myeloid neoplasms

Leukemia volume 36, pages 126–137 (2022)Cite this article

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Abstract

The germline predisposition associated with the autosomal dominant inheritance of the 14q32 duplication implicating ATG2B/GSKIP genes is characterized by a wide clinical spectrum of myeloid neoplasms. We analyzed 12 asymptomatic carriers and 52 patients aged 18–74 years from six families, by targeted sequencing of 41 genes commonly mutated in myeloid malignancies. We found that 75% of healthy carriers displayed early clonal hematopoiesis mainly driven by TET2 mutations. Molecular landscapes of patients revealed two distinct routes of clonal expansion and leukemogenesis. The first route is characterized by the clonal dominance of myeloproliferative neoplasms (MPN)-driver events associated with TET2 mutations in half of cases and mutations affecting splicing and/or the RAS pathway in one-third of cases, leading to the early development of MPN, mostly essential thrombocythemia, with a high risk of transformation (50% after 10 years). The second route is distinguished by the absence of MPN-driver mutations and leads to AML without prior MPN. These patients mostly harbored a genomic landscape specific to acute myeloid leukemia secondary to myelodysplastic syndrome. An unexpected result was the total absence of DNMT3A mutations in this cohort. Our results suggest that the germline duplication constitutively mimics hematopoiesis aging by favoring TET2 clonal hematopoiesis.

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Fig. 1: Pedigrees of the six families linked to the germline CNVdupATG2B/GSKIP.
Fig. 2: Characteristics of clonal hematopoiesis in asymptomatic carriers of the CNVdupATG2B/GSKIP.
Fig. 3: Clonal phylogeny of seven patients with ET.
Fig. 4: Effects of genomic acquired factors on the risk of progression of ET patients.
Fig. 5: Disease penetrance and schematic representation of the two alternative routes of leukemogenesis associated with the germline CNVdupATG2B/GSKIP locus.

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Acknowledgements

We thank all the patients and family members involved in the study. This work was supported by INSERM, Gustave Roussy and grants from Program Hospitalier de Recherche Clinique (PHRC) AOR07014 (CB-C and AN), INCa Plbio2017 (IP and FD), Journées Nationales Contre la Leucémie (IP and J-BM), and Association sur la recherche pour le cancer (Program Labellisé Fondation ARC PGA2020 to IP). BS-P was supported by Association de Recherche sur la Moelle Osseuse (ARMO) and INCa Plbio2017. CB-C is a recipient from contrat d’interface INSERM.

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  1. These authors contributed equally: Jean Pegliasco, Pierre Hirsch.

Authors and Affiliations

  1. INSERM, U1287, Gustave Roussy, Villejuif, France

    Jean Pegliasco, Christophe Marzac, Graciela Rabadan Moraes, Barbara Schmaltz-Panneau, William Vainchenker, Jean-Baptiste Micol, Isabelle Plo & Christine Bellanné-Chantelot

  2. Université Paris-Saclay, Gustave Roussy, Villejuif, France

    Jean Pegliasco, Christophe Marzac, Barbara Schmaltz-Panneau, Florence Pasquier, William Vainchenker, Jean-Baptiste Micol & Isabelle Plo

  3. Département d’Hématologie, Gustave Roussy, Villejuif, France

    Jean Pegliasco, Florence Pasquier, Jean-Henri Bourhis, Samy Chraibi & Jean-Baptiste Micol

  4. Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, AP-HP, Hôpital Saint-Antoine, Hématologie Biologique, Paris, France

    Pierre Hirsch, Caroline Deswarte, Hélène Guermouche & François Delhommeau

  5. Département de Biologie et Pathologie Médicales, Gustave Roussy, Villejuif, France

    Christophe Marzac

  6. AP-HP, Hôpital Saint-Antoine, Service d’Hématologie Clinique et de Thérapie Cellulaire, Sorbonne Université, Paris, France

    Françoise Isnard, Eolia Brissot, Simona Lapusan & Albert Najman

  7. Martinique University Hospital, Fort-de-France, Martinique, France

    Jean-Côme Meniane

  8. Département de Génétique Médicale, Sorbonne Université, AP-HP, Hôpital Pitié-Salpêtrière, DMU BioGeM, Paris, France

    Philippe Pellet, Céline Lemaitre, Gwendoline Leroy, Chrystelle Colas, Patrick R. Benusiglio & Christine Bellanné-Chantelot

  9. Université Paris Diderot, Gustave Roussy, Villejuif, France

    Graciela Rabadan Moraes

  10. Département de Génétique, Institut Curie, Université Paris Sciences Lettres, Paris, France

    Chrystelle Colas

  11. Department of Medical Biology, Martinique University Hospital, Fort-de-France, Martinique, France

    Odile Bera & Pascal Fuseau

  12. Département de médecine oncologique, Gustave Roussy, Université Paris-Saclay, Villejuif, France

    Olivier Caron

  13. Centre hospitalier Annecy-Genevois, Pringy, France

    Pascale Cony-Makhoul

  14. Centre hospitalier du Lamentin, Lamentin, Martinique, France

    Christine Delaunay-Darivon

  15. AP-HP, Hôpital Saint-Louis, Service d’Hématologie-Greffe, Paris, France

    Flore Sicre de Fontbrune

  16. Département d’Immunologie Clinique, AP-HP, Hôpital Saint-Louis, Paris, France

    William Vainchenker

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  1. Jean Pegliasco
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Contributions

IP and CB-C designed the research, analyzed data, prepared figures, and wrote the paper. JP collected data, analyzed results, and prepared figures. PH, FI, J-CM, FP, J-HB, EB, OC, SC, PC-M, CD-D, SL, FS-F, PF, WV, and J-BM were involved in the clinical aspects of the study. CC, PRB, and OB performed the genetic counseling. A.N. was involved in the clinical aspect of the study and initiated the familial study of MPN. PH, CM, CD, and FD performed and analyzed the NGS. PP, CL, and GL performed DNA extraction, CNV, and SNV genotyping, Sanger sequencing, and analyzed results. GR-M. and BS-P purified primary cells from patients. PH conducted the statistical analysis. PH, WV, FD, and J-BM contributed intellectual input. All authors critically reviewed and approved the final version of the manuscript.

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Correspondence to Christine Bellanné-Chantelot.

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Pegliasco, J., Hirsch, P., Marzac, C. et al. Germline ATG2B/GSKIP-containing 14q32 duplication predisposes to early clonal hematopoiesis leading to myeloid neoplasms. Leukemia 36, 126–137 (2022). https://doi.org/10.1038/s41375-021-01319-w

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