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In hematopoietic cells with a germline mutation of CBL, loss of heterozygosity is not a signature of juvenile myelo-monocytic leukemia

Leukemia volume 27, pages 2404–2407 (2013)Cite this article

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The CBL gene (11q23.3) encodes an E3 ubiquitin ligase that negatively regulates signaling by promoting degradation of activated tyrosine kinase receptors. In addition, CBL is an adaptor protein that positively regulates signal transduction.1 Individuals with germline heterozygous CBL mutations present with a clinically variable condition that can resemble Noonan syndrome and will be further referred as the ‘CBL syndrome.’ 2These patients are at increased risk of developing juvenile myelo-monocytic leukemia (JMML), an aggressive myelodysplastic and myeloproliferative neoplasm of early childhood characterized by clonal macrophage/monocyte proliferation.3, 4 JMML cells are hypersensitive to granulocyte–macrophage colony-stimulating factor consecutively to the activation of the RAS-MAPK signaling pathway through the mutation of the following genes: PTPN11, NRAS, KRAS, NF1 or CBL. CBL-associated JMML can follow an aggressive clinical course or resolve without treatment.4, 5, 6 The current diagnostic criteria for JMML are based on an international consensus that recently incorporated NF1, RAS and PTPN11 mutational status and monosomy 7.7 CBL mutations have since been discovered and are also screened for in the workup of patients with suspected JMML.8, 9 CBL mutations reported so far are missense mutations or splice site variants clustered in the linker region, and at or near the zinc-coordinating amino acids of the RING finger domain.1 They all result in the expression of a CBL protein with defective E3 ligase activity that constitutively activates key RAS effector pathways.4 Importantly, in virtually all patients described so far, the wild-type CBL allele is lost in leukemic cells and replaced with the mutant allele by acquired uniparental isodisomy of the 11q23 chromosomal region leading to loss of heterozygosity (LOH) of the mutated CBL.4, 3, 6 Hence, LOH of the mutated CBL in hematopoietic cells is usually considered as a signature of JMML in patients with ‘CBL syndrome.’ However, to date, consequences induced by LOH of CBL mutant proteins remain partly unknown.

CBL mutations were screened in JMML patients of the French cohort (n=102) and in patients referred to our lab with a borderline JMML phenotype. The diagnosis of JMML was based on consensus criteria as described above and included centralized cytomorphological review of bone marrow and blood as well as a comprehensive genetic testing by bidirectional Sanger sequencing of tumoral DNA.5, 7 CBL mutations were identified in a total of 12 children. The germline origin of mutations was tested on constitutional DNA (fibroblasts and/or nails). 11q23 LOH was explored on tumor cells DNA paired with germline DNA by PCR analysis of microsatellite markers covering the 11q23 region and/or genome-wide single-nucleotide polymorphism (SNP)-array analysis (GeneChip Human SNP-Array 6.0, Affimetrix, Santa Clara, CA, USA).5 In vitro growth of myeloid progenitors from bone marrow was found positive in all CBL mutated patients who were tested (Table 1).10

Table 1 Patients with CBL mutation
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Acknowledgements

SNP arrays were performed on the Plateforme de Génomique du GHU Nord and analyzed with the help of Steven Gazal. We thank Dr Franck Bourdeault (Institut Curie, Paris, France) for analysis of the rhabdomyosarcoma sample.

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Authors and Affiliations

  1. Department of Genetics, Assistance Publique-Hôpitaux de Paris (AP-HP) Robert Debré Hospital, Paris, France

    M Strullu, A Caye & H Cavé

  2. INSERM UMR_S940, Institut Universitaire d’Hématologie (IUH), Université Paris-Diderot Sorbonne-Paris-Cité, Paris, France

    M Strullu, A Caye, B Cassinat, C Chomienne & H Cavé

  3. Cellular Biology Unit, Assistance Publique-Hôpitaux de Paris (AP-HP) Saint-Louis Hospital, Paris, France

    B Cassinat & C Chomienne

  4. Biological Hematology Laboratory, (AP-HP) Robert Debré Hospital, Paris, France

    O Fenneteau

  5. Department of Biotherapy, Assistance Publique-Hôpitaux de Paris (AP-HP) Necker Hospital, Paris, France

    F Touzot

  6. Department of Pediatric Neurosurgery, Assistance Publique-Hôpitaux de Paris (AP-HP) Necker Hospital, Paris, France

    T Blauwblomme

  7. INSERM U768, Necker Hospital, University Paris-Descartes Sorbonne-Paris-Cité, Institut Imagine, Paris, France

    R Rodriguez & S Latour

  8. Department of Pediatric Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP) Trousseau Hospital, Paris, France

    A Petit

  9. Department of Pediatric Hematology, La Timone Hospital, Marseille, France

    V Barlogis & C Galambrun

  10. Department of Pediatric Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP) Robert Debré Hospital, Paris, France

    T Leblanc & A Baruchel

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Correspondence to H Cavé.

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Strullu, M., Caye, A., Cassinat, B. et al. In hematopoietic cells with a germline mutation of CBL, loss of heterozygosity is not a signature of juvenile myelo-monocytic leukemia. Leukemia 27, 2404–2407 (2013). https://doi.org/10.1038/leu.2013.203

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