We present the case of a child with JMML in the setting of germline PTPN11 mutation and Noonan syndrome with suspected secondary development of monosomy 7 in the bone marrow.
Genome-wide single-nucleotide polymorphism analysis in juvenile myelomonocytic leukemia identifies uniparental disomy surrounding the NF1 locus in cases associated with neurofibromatosis but not in cases with mutant RAS or PTPN11.
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.
In summary, our data indicate that a mitotic recombination event in a JMML-initiating cell led to 17q UPD with homozygous loss of normal NF1, provide confirmatory evidence that the NF1 gene is crucial for the increased incidence of JMML in NF-1 patients, and corroborate the concept that RAS pathway deregulation is central to JMML pathogenesis.
We report the first case of LIP in a patient with juvenile myelomonocytic leukemia (JMML) who was found to have a novel germline mutation of unknown significance in additional sex combs-like-1 (ASXL1) gene and a pathogenic somatic mutation of protein tyrosine phosphatase, nonreceptor type 11 (PTPN11) gene at diagnosis.
Given the association between NS and an increased risk of some malignancies, notably leukemia and probably some solid tumors including neuroblastoma (NB) and rhabdomyosarcoma (RMS), recent studies have reported that gain-of-function somatic mutations in PTPN11 occur in some hematological malignancies, especially de novo juvenile myelomonocytic leukemia (JMML) and in some solid tumors such as NB, although at a low frequency.
The transient thrombocythemia may relate to a regulator of megakaryocytopoiesis located in the vicinity of the NF1 gene or to the excessive risk of chronic myelomonocytic leukemia in neurofibromatosis.
Mutations and other genetic abnormalities of RAS, NF1, and PTPN11 have been implicated as causative events in JMML, but approximately 25% of JMML patients harbor none of these abnormalities.
Juvenile Myelomonocytic Leukemia (JMML) is a relentlessly progressive myeloproliferative/myelodysplastic (MPD/MDS) hematopoietic disorder more common in patients with any one of at least three distinct genetic lesions, specifically NF1 gene loss and PTPN11 and NRAS mutations.
Of 11 children with juvenile myelomonocytic leukemia (JMML) carrying RAS mutations (8 with NRAS mutations, 3 with KRAS2 mutations), 5 had a profound elevation in either or both the white blood cells and spleen size at diagnosis.
Somatic defects in either RAS, PTPN11 or NF1 genes involved in this pathway are detected in 70-80% of JMML patients, allowing a molecular diagnosis to be made in the majority of cases.
Von Recklinghausen's disease is a relatively common familial genetic disorder characterized by inactivating mutations of the Neurofibromatosis-1 (NF1) gene that predisposes these patients to malignancies, including an increased risk for juvenile myelomonocytic leukemia.
Other mutations of putative pathogenetic relevance in MPDs include: JAK2V617F in PV, ET, and PMF; JAK2 exon 12 mutations in PV; MPLW515L/K in PMF and ET; KITD816V in SM; FIP1L1-PDGFRA in CEL-SM; rearrangements of PDGFRB in CEL-CMML and FGFR1 in stem cell leukemia-lymphoma syndrome; and RAS/PTPN11/NF1 mutations in JMML.
Juvenile Myelomonocytic Leukemia (JMML) is a relentlessly progressive myeloproliferative/myelodysplastic (MPD/MDS) hematopoietic disorder more common in patients with any one of at least three distinct genetic lesions, specifically NF1 gene loss and PTPN11 and NRAS mutations.