Germline mutations of the CBL gene define a new genetic syndrome with predisposition to juvenile myelomonocytic leukemia (JMML)

Benoite Pérez (1, 2) , Françoise Mechinaud (3) , Claire Galambrun (4) , Neila Benromdhan (5) , Bertrand Isidor (6) , Nicole Philip (7) , Justine Derain-Court (7) , Bruno Cassinat (1) , Julie Lachenaud (1, 2) , Sophie Kaltenbach (2) , Christel Désirée (2) , Sabrina Pereira (2) , Marie-Laurence Menot (1) , Nicolas Royer (8) , Odile Fenneteau (9) , André Baruchel (10) , Christine Chomienne (1) , Alain Verloes (1, 2) , Hélène Cavé (1, 2)

1 Hématologie -Immunologie -Cibles thérapeutiques
2 Service de génétique clinique
3 Service d'Oncologie Hématologie Pédiatrique
4 Service d'Hématologie pédiatrique
5 Service d'Hématologie
6 Service de génétique médicale - Unité de génétique clinique [Nantes]
7 Service de Génétique
8 Service de biochimie-hormonologie
9 Service d'Hématologie Biologique [Hôpital Robert Debré, Paris]
10 Service d'hématologie et immunologie pédiatrique

Background: CBL missense mutations have recently been associated with juvenile myelomonocytic leukemia (JMML), an aggressive myeloproliferative and myelodysplatic neoplasm of early childhood characterized by excessive macrophage/monocyte proliferation. CBL, an E3 ubiquitin ligase and a multi adaptor protein, controls proliferative signaling networks by downregulating the growth factor receptor signaling 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 leukemic cells of 4/65 (6%) patients. In all cases, copy neutral loss of heterozygosity of the 11q23-qter chromosomal region, encompassing the CBL locus, was demonstrated. Three of these 4 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 3 patients display a variable combination of dysmorphic features, hyperpigmented skin lesions and microcephaly that allow us to tentatively delineate a "CBL syndrome". Learning difficulties and postnatal growth retardation may be part of the phenotype. Conclusion: We report germline mutations of CBL in 3 patients with JMML, confirming the existence of an unreported inheritable condition associated with a predisposition to JMML.

Mots clés: Molecular genetics; Haematology (incl Blood transfusion); Paediatric oncology

Benoite Pérez, Françoise Mechinaud, Claire Galambrun, Neila Benromdhan, Bertrand Isidor, et al.. Germline mutations of the CBL gene define a new genetic syndrome with predisposition to juvenile myelomonocytic leukemia (JMML). Journal of Medical Genetics, 2010, 47 (10), pp.686. ⟨10.1136/jmg.2010.076836⟩. ⟨hal-00557393⟩