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Germline mutations of the CBL gene define a new genetic syndrome with predisposition to juvenile myelomonocytic leukaemia
  1. B Pérez1,2,
  2. F Mechinaud3,
  3. C Galambrun4,
  4. N Ben Romdhane5,
  5. B Isidor6,
  6. N Philip7,
  7. J Derain-Court7,
  8. B Cassinat2,
  9. J Lachenaud1,2,
  10. S Kaltenbach1,
  11. A Salmon8,
  12. C Désirée1,
  13. S Pereira1,
  14. M L Menot2,
  15. N Royer9,
  16. O Fenneteau10,
  17. A Baruchel11,
  18. C Chomienne2,
  19. A Verloes1,12,
  20. H Cavé1,2
  1. 1APHP, Hôpital Robert Debré, Département de Génétique; Université Paris 7-Denis Diderot, Paris, France
  2. 2INSERM U940, Institut Universitaire d'Hématologie (IUH), Hôpital Saint Louis, Paris, France
  3. 3Service d'Oncologie Hématologie Pédiatrique, CHRU, Nantes, France
  4. 4Service d'Hématologie Pédiatrique, Hôpital de la Timone, Marseille, France
  5. 5Service d'Hématologie, Hopital La Rabta, Tunis
  6. 6Service de Génétique, CHRU, Nantes, France
  7. 7Service de Génétique, Hôpital de la Timone, Marseille, France
  8. 8Service d'Onco-Hématologie Pédiatrique, CHRU, Nancy, France
  9. 9APHP, Hôpital Robert Debré, Service de Biochimie-Hormonologie, Paris, France
  10. 10APHP, Hôpital Robert Debré, Service d'Hématologie Biologique, Paris, France
  11. 11APHP, Hôpital Robert Debré, Service d'Hématologie Pédiatrique; Université Paris 7-Denis Diderot, Paris, France
  12. 12INSERM U676, Hôpital Robert Debré, Paris, France
  1. Correspondence to Dr Hélène Cavé, Laboratoire de Biochimie Génétique, Hôpital Robert Debré, 48, Boulevard Sérurier, 75019 Paris, France; helene.cave{at}


Background CBL missense mutations have recently been associated with juvenile myelomonocytic leukaemia (JMML), an aggressive myeloproliferative and myelodysplastic neoplasm of early childhood characterised by excessive macrophage/monocyte proliferation. CBL, an E3 ubiquitin ligase and a multi-adaptor protein, controls proliferative signalling networks by downregulating the growth factor receptor signalling cascades in various cell types.

Methods and results CBL mutations were screened in 65 patients with JMML. A homozygous mutation of CBL was found in leukaemic cells of 4/65 (6%) patients. In all cases, copy neutral loss of heterozygosity of the 11q23 chromosomal region, encompassing the CBL locus, was demonstrated. Three of these four patients displayed additional features suggestive of an underlying developmental condition. A heterozygous germline CBL p.Y371H substitution was found in each of them and was inherited from the father in one patient. The germline mutation represents the first hit, with somatic loss of heterozygosity being the second hit positively selected in JMML cells. The three patients display a variable combination of dysmorphic features, hyperpigmented skin lesions and microcephaly that enable a ‘CBL syndrome’ to be tentatively delineated. Learning difficulties and postnatal growth retardation may be part of the phenotype.

Conclusion A report of germline mutations of CBL in three patients with JMML is presented here, confirming the existence of an unreported inheritable condition associated with a predisposition to JMML.

  • JMML
  • CBL
  • microcephaly
  • cancer predisposition
  • molecular genetics
  • haematology (incl blood transfusion)
  • paediatric oncology

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  • Competing interests None.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.