PTPN11 mutation with additional alterations showed significantly the poorest outcome in comparison with those with only one non-PTPN11 mutation, only one PTPN11 mutation, and combined mutations without PTPN11, respectively (P < 0.0001).Conclusion: Both PTPN11 mutation and the number of somatic alterations detected at diagnosis are likely to be the major determinant of outcome in JMML.
We have previously shown that MYC is involved in the differential gene expression observed in Noonan syndrome patients associated with an increased incidence of JMML.
Transduction of the PTPN11 mutation into JMML iPSCs with the wild-type of both genes increased CD34<sup>+</sup> cell production to a level comparable to that obtained with JMML iPSC colonies harbouring the two genetic mutations.
Zinc-finger nuclease-mediated homologous recombination revealed that correction of PTPN11 mutation in iPSCs with PTPN11 and OSBP2 mutations resulted in reduced CD34<sup>+</sup> cell generation to a level similar to that obtained with JMML iPSC colonies with the wild-type of both genes, and interestingly, to that obtained with normal iPSC colonies.
Finally, we prove the clinical relevance of these findings by showing that RKIP loss is a frequent event in chronic myelomonocytic leukemia, and that it co-occurs with <i>RAS</i>-signaling mutations.
Germline pathogenic variants in CBL are associated with an autosomal dominant RASopathy and an increased risk for malignancies, particularly juvenile myelomonocytic leukemia.
Here, we report that impaired GATA2 expression induces myelodysplastic and myeloproliferative neoplasm development in elderly animals, and this neoplasm resembles chronic myelomonocytic leukemia in humans.
Platelet-derived growth factor receptor beta (PDGFRB) rearrangement has been reported in a number of patients with chronic eosinophilic leukemia (CEL), B-acute lymphoblastic leukemia, myeloproliferative neoplasms, and juvenile myelomonocytic leukemia.
Mixed lineage leukemia [MLL; now known as lysine methyltransferase 2A (KMT2A)] rearrangement-positive acute myeloid leukemia (AML) and juvenile myelomonocytic leukemia (JMML) are distinct diseases, although age of susceptibility (infancy or early childhood) and abnormal monocytosis are common clinical features.
Chemical inhibition of TNK2 blocked MAPK signaling and colony formation in vitro and decreased disease burden in a patient with PTPN11-mutant JMML who was treated with the multikinase (including TNK2) inhibitor dasatinib.
Chemical inhibition of TNK2 blocked MAPK signaling and colony formation in vitro and decreased disease burden in a patient with PTPN11-mutant JMML who was treated with the multikinase (including TNK2) inhibitor dasatinib.
We previously reported that stimulation of JMML CD34<sup>+</sup> cells with stem cell factor and thrombopoietin on irradiated murine AGM-S3 cells led to substantial expansion of JMML CD34<sup>+</sup> cells that contained leukemic stem cells capable of transplantation into immunodeficient mice.
Juvenile myelomonocytic leukemia in the patient was attributed to a somatic KRAS mutation, whereas the syndromic features of the patient were considered a consequence of germline chromosome 10q22.3-q23.2 deletion.
We used patient-derived induced pluripotent stem cells (iPSCs) to characterize the signaling profiles and potential therapeutic vulnerabilities of PTPN11-mutant and CBL-mutant JMML.