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PTPN11 mutations in childhood acute lymphoblastic leukemia occur as a secondary event associated with high hyperdiploidy

Leukemia volume 24, pages 232–235 (2010)Cite this article

The protein tyrosine phosphatase, non-receptor type 11 (PTPN11) gene encodes SHP-2, a phosphatase involved in many signaling pathways, with a key role in development and hematopoiesis. Somatic PTPN11 mutations were found with variable prevalences in pediatric leukemia, most frequently associated with juvenile myelomonocytic leukemia (JMML).1, 2 In vitro and in vivo studies, mainly in a myeloid context, demonstrated a crucial involvement of PTPN11 mutations in the hyperactivation of the RAS/ERK pathway.3 The oligoclonality of transgene integration sites, and the long latency before overt leukemia in mice transduced with mutant PTPN11,3 suggested that additional molecular lesions are needed to cooperate with PTPN11 mutations in leukemogenesis. This observation is in line with the ‘two hit model’ proposed by Greaves4 for B-cell precursor childhood acute lymphoblastic leukemia (ALL), in which an initiating alteration, often occurring prenatally, gives rise to a preleukemic clone, which eventually becomes fully malignant by subsequent acquisition of other molecular alterations.

We previously documented that somatically acquired PTPN11 mutations occur in approximately 10% of B-cell precursor childhood ALL.2 Molecular profiling indicated that PTPN11 mutations were largely mutually exclusive with NRAS and KRAS mutations, suggesting a perturbing role of PTPN11 mutations on signal flow through RAS in ALL as well. In childhood ALL, high hyperdiploidy (>50 chromosomes) is the most frequent cytogenetic aberration, accounting for 30% of the cases.5 Although several lines of evidence support the view that hyperdiploidy is an early leukemogenic event, frequently occurring prenatally,6 the long latency before overt leukemia strongly indicates that, also for hyperdiploidy, additional alterations in the leukemic clone are required.6 Although a higher prevalence of mutations in genes coding for transducers with a role in RAS signaling in high hyperdiploid childhood ALL cases has been reported,7, 8 the order of the events before overt disease in PTPN11-mutated ALL has not been addressed.

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Acknowledgements

We thank Silvia Bungaro for FISH analysis and help in SNP array preparation and analyses, and Paola De Lorenzo for statistical analyses. This work was partially supported by Fondazione Cariplo, AIRC, MIUR and Associazione Genitori Onco-Ematologia Pediatrica ‘Per un Sorriso in piú’.

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Author notes

  1. A Biondi and G Cazzaniga: AB and GC share the seniorship of this paper.

Authors and Affiliations

  1. Centro Ricerca Tettamanti, Clinica Pediatrica Università Milano-Bicocca, Ospedale San Gerardo, Monza, Italy

    C G Molteni, T Villa, A Biondi & G Cazzaniga

  2. Laboratorio di Onco-Ematologia, Clinica Pediatrica, Università di Padova, Padua, Italy

    G te Kronnie & G Basso

  3. Dipartimento di Scienze Biomediche, Università di Modena e Reggio Emilia, Modena, Italy

    S Bicciato

  4. Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, Rome, Italy

    M Tartaglia

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Correspondence to G Cazzaniga.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Molteni, C., te Kronnie, G., Bicciato, S. et al. PTPN11 mutations in childhood acute lymphoblastic leukemia occur as a secondary event associated with high hyperdiploidy. Leukemia 24, 232–235 (2010). https://doi.org/10.1038/leu.2009.200

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