The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease

Abstract

Germ line PTPN11 mutations cause 50% of cases of Noonan syndrome (NS). Somatic mutations in PTPN11 occur in 35% of patients with de novo, nonsyndromic juvenile myelomonocytic leukemia (JMML). Myeloproliferative disorders (MPDs), either transient or more fulminant forms, can also occur in infants with NS (NS/MPD). We identified PTPN11 mutations in blood or bone marrow specimens from 77 newly reported patients with JMML (n ‫؍‬ 69) or NS/MPD (n ‫؍‬ 8). Together with previous reports, we compared the spectrum of PTPN11 mutations in 3 groups: (1) patients with JMML (n ‫؍‬ 107); (2) patients with NS/MPD (n ‫؍‬ 19); and (3) patients with NS (n ‫؍‬ 243). Glu76 was the most commonly affected residue in JMML (n ‫؍‬ 45), with the Glu76Lys alteration (n ‫؍‬ 29) being most frequent. Eight of 19 patients with NS/ MPD carried the Thr73Ile substitution. These data suggest that there is a genotype/phenotype correlation in the spectrum of PTPN11 IntroductionThe PTPN11 proto-oncogene encodes Src-homology tyrosine phosphatase 2 (SHP-2), a protein tyrosine phosphatase with a role in signal transduction and hematopoiesis. 1,2 Somatic PTPN11 mutations exist in 35% of juvenile myelomonocytic leukemia (JMML) specimens and are less frequent in other leukemias. 3-6 SHP-2 relays signals from activated growth factor receptors to Ras. PTPN11, KRAS2, NRAS, and NF1 mutations are found in mutually exclusive subsets of patients with JMML. 3,4 These data support the hypothesis that hyperactive Ras signaling plays a central role in JMML.Germ-line PTPN11 mutations cause approximately 50% of cases of Noonan syndrome (NS), 7,8 a congenital disorder characterized by facial anomalies, short stature, and heart defects. 9 Whereas NS is frequently inherited as an autosomal dominant condition, almost half of the constitutional PTPN11 mutations found in NS arise sporadically. Germ-line PTPN11 mutations are also found in patients with multiple lentigene syndrome (LS), a rare developmental disorder clinically related to NS. 9 Infants with NS are predisposed to developing a myeloproliferative disorder (NS/MPD), which may regress without treatment or follow an aggressive clinical course similar to JMML. 10-14 By contrast, cases of JMML that arise in patients without NS have a poor prognosis without hematopoietic stem cell transplantation. [15][16][17][18] Recent studies show that children with JMML have improved outcomes when they are treated aggressively early in the course of disease. 18 Therefore, differentiating JMML from NS/MPD and identifying patients with NS/MPD who will require aggressive treatment are important clinical questions. We identify PTPN11 mutations in 77 newly reported patients with JMML and NS/MPD, and compare the mutational spectrum in JMML, NS/MPD, and NS/LS to determine if genotype-phenotype correlations exist that may help guide diagnosis and clinical management. Study designTissue samples (bone marrow, peripheral blood, and, rarely, buccal swab and skin fibroblasts) from patients with JMML and NS/MPD were collected under Institutional...

Molecular determinants of pathogenesis and clinical phenotype in myeloproliferative neoplasms

“…These mutations appear to result in a gain-of-function, resulting in myeloid differentiation and increased HSC self-renewal, and can induce a chronic myelomonocytic leukemia (CMML)-like disease in a mouse model. 61 Similarly, negative regulators of RAS, such as NF1 62 and PTPN11, 63 have also been found to be mutated in some MPN or MPN/MDS-overlap cases.…”

CBL Linker Region and RING Finger Mutations Lead to Enhanced Granulocyte-Macrophage Colony-stimulating Factor (GM-CSF) Signaling via Elevated Levels of JAK2 and LYN

“…10 -15% of JMML patients harbor mutations in neuro-fibromin protein (NF1) (9, 10), a GTPase-activating protein, which negatively regulates RAS by enhancing the hydrolysis of the active GTP-bound conformation of RAS to the inactive GDP-bound form (11). 35% of JMML patients have mutations in SHP2 (12)(13)(14), a protein-tyrosine phosphatase that positively regulates the RAS signaling pathway (15,16). RAS-activating mutations account for another 20 -25% of JMML-associated mutations (17)(18)(19).…”

Juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia

“…55,56 Somatic mutations in PTPN11 represent the most frequent molecular lesion identified to date in JMML, with up to 35% of JMML cases demonstrating PTPN11 mutations, often mutually exclusive with RAS or NF1 mutations. [57][58][59][60][61] Mouse models of these genetic lesions have proven their causal role in myeloproliferative disease development as well as hyperactivation of the Ras pathway and GM-CSF hypersensitivity. [62][63][64][65][66][67] The interested reader can see one of several recent reviews for a more in-depth review of these biochemical and genetic aberrations.…”