Gain-of-function variants in some RAS-MAPK pathway genes, including PTPN11 and NRAS, are associated with RASopathies and/or acquired hematological malignancies, most notably juvenile myelomonocytic leukemia (JMML).
SHP2 has emerged as an attractive target for therapeutic targeting in hematological malignancies for its cell autonomous and microenvironmental effects.
The PTPN11 oncogene encodes the cytoplasmic protein tyrosine phosphatase SHP2, which, through its role in multiple signaling pathways, promotes the progression of hematological malignancies and other cancers.
Germline and somatic mutations in PTPN11 are involved in Noonan syndrome (NS), LEOPARD syndrome (LS), and hematological malignancies, as well as several solid tumors.
We analyzed 77 samples from hematologic malignancies, identifying a somatic mutation in CBL (p.C381R) in one patient with T-ALL that was associated with a uniparental disomy at the CBL locus and a germline heterozygous mutation in one patient with JMML.
Somatic PTPN11 mutations contribute to leukemogenesis in children with hematologic malignancies including juvenile myelomonocytic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, and myelodysplasia.
Wild type SHP-2 and four disease-associated mutants recurring in hematologic malignancies (Glu76Lys and Ala72Val) or causing NS (Glu76Asp and Ala72Ser), with affected residues located in the PTP-interacting region of the N-SH2 domain, were analyzed by molecular dynamics simulations and in vitro biochemical assays.
Our data suggest that mutations of PTPN11 as well as RAS play a role in the pathogenesis of not only myeloid hematological malignancies but also a subset of RMS malignancies.
We recently demonstrated that acquired mutations in PTPN11 are a major event in JMML and occur with variable prevalence in children with other hematologic malignancies, including MDS.
Fully characterizing the incidence and spectrum of PTPN11 mutations in hematologic malignancies, and in other forms of cancer, is an area of active investigation.
Somatic PTPN11 mutations are common in patients with juvenile myelomonocytic leukemia (JMML) and have been reported in some other hematologic malignancies.