The PTPN11 gene encodes SHP-2 (Src homology 2 domain-containing protein tyrosine Phosphatase), a nonreceptor tyrosine protein tyrosine phosphatase (PTPase) that relays signals from activated growth factor receptors to p21 Ras (Ras) and other signaling molecules. Mutations in PTPN11 cause Noonan syndrome (NS), a developmental disorder characterized by cardiac and skeletal defects. NS is also associated with a spectrum of hematologic disorders, including juvenile myelomonocytic leukemia (JMML). To test the hypothesis that PTPN11 mutations might contribute to myeloid leukemogenesis, we screened the entire coding region for mutations in 51 JMML specimens and in selected exons from 60 patients with other myeloid malignancies. Missense mutations in PTPN11 were detected in 16 of 49 JMML specimens from patients without NS, but they were less common in other myeloid malignancies. RAS, NF1, and PTPN11 mutations are largely mutually exclusive in JMML, which suggests that mutant SHP-2 proteins deregulate myeloid growth through Ras. However, although Ba/F3 cells engineered to express leukemia-associated SHP-2 proteins cells showed enhanced growth factor-independent survival, biochemical analysis failed to demonstrate hyperactivation of the Ras effectors extracellular-regulated kinase (ERK) or Akt. We conclude that SHP-2 is an important cellular PTPase that is mutated in myeloid malignancies. Further investigation is required to clarify how these mutant proteins interact with Ras and other effectors to deregulate myeloid growth. (Blood.

PTPN11 encodes the protein tyrosine phosphatase SHP-2, which relays signals from growth factor receptors to Ras and other effectors. Germline PTPN11 mutations underlie about 50% of Noonan syndrome (NS), a developmental disorder that is associated with an elevated risk of juvenile myelomonocytic leukemia (JMML). Somatic PTPN11 mutations were recently identified in about 35% of patients with JMML; these mutations introduce amino acid substitutions that are largely distinct from those found in NS.We assessed the functional consequences of leukemia-associated PTPN11 mutations in murine hematopoietic cells. Expressing an E76K SHP-2 protein induced a hypersensitive pattern of granulocyte-macrophage colony-forming unit (CFU-GM) colony growth in response to granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 3 (IL-3) that was dependent on SHP-2 catalytic activity. E76K SHP-2 expression also enhanced the growth of immature progenitor cells with high replating potential, perturbed erythroid growth, and impaired normal differentiation in liquid cultures. In addition, leukemia-associated SHP-2 mutations conferred a stronger phenotype than a germline mutation found in patients with NS. Mutant SHP-2 proteins induce aberrant growth in multiple hematopoietic compartments, which supports a primary role of hyperactive Ras in the pathogenesis of JMML. IntroductionThe PTPN11 gene encodes SHP-2, a nonreceptor tyrosine phosphatase (PTPase) that relays signals from activated growth factor receptors to p21 ras (Ras), Src family kinases, and other signaling molecules (for reviews, see Barford and Neel 1 and Neel et al 2 ). SHP-2 contains 2 Src homology 2 (SH2) domains and a catalytic PTPase domain. The SHP-2 crystal structure predicts that binding of the N-SH2 domain to phosphotyrosyl peptides results in a conformational shift that relieves inhibition of the PTPase and activates SHP-2 function. 3 Missense mutations in PTPN11 underlie about 50% of cases of Noonan syndrome (NS), a developmental disorder characterized by cardiac defects, facial dysmorphism, and skeletal malformations. 4 Most of the PTPN11 mutations found in NS introduce amino acid substitutions within the N-SH2 and PTPase domains. 4,5 Molecular modeling and biochemical data infer that exon 3 mutations dominantly activate SHP-2 phosphatase activity by altering critical N-SH2 amino acids that lie on the interface with the PTPase domain. 4,5 Infants with NS show a spectrum of hematologic abnormalities that includes isolated monocytosis as well as myeloid disorders with features of chronic myelomonocytic leukemia that may remit spontaneously. [6][7][8] Patients with NS are also predisposed to juvenile myelomonocytic leukemia (JMML), an aggressive myeloproliferative disorder (MPD) characterized by leukocytosis, tissue infiltration, and hypersensitivity to granulocyte-macrophage colonystimulating factor (GM-CSF). 9,10 Studies of JMML specimens and experiments in mutant strains of mice strongly implicate aberrant Ras signaling in response to GM-CSF and othe...

Hemophilia A (HA) is a common bleeding disorder caused by the deficiency of factor VIII (FVIII) with an incidence of ~1 in 5000 male births. Replacement of FVIII is necessary to prevent and treat bleeding episodes. However, with multiple new drugs in addition to old standards, choosing among the different FVIII treatment options is harder than ever. There are FVIII products that are plasma derived or recombinant, FVIII products designed to extend the half-life of FVIII, and the first single-chain FVIII product, recombinant factor VIII single chain (rFVIII-SC). As development of inhibitors to FVIII continues to be a major problem in the care of HA patients, recent studies showing lower rates of inhibitor development with plasma-derived FVIIII products versus recombinant FVIII products have made choosing among the many options now available even more complex. Although still unproven, extended half-life (EHL) products may provide the hope of decreased immunogenicity but need further testing in previously untreated patients (PUPs). This review highlights some of the differences between FVIII products currently available and hopefully assists the clinician to decide which FVIII product to choose for their patients.

Introduction Immune tolerance induction (ITI) is the gold standard for eradication of factor VIII inhibitors in severe haemophilia A; however, it usually requires treatment for extended periods with associated high burden on patients and healthcare resources. Aim Review outcomes of ITI with recombinant factor VIII Fc fusion protein (rFVIIIFc) in patients with severe haemophilia A and high‐titre inhibitors. Methods Multicentre retrospective chart review of severe haemophilia A patients treated with rFVIIIFc for ITI. Results Of 19 patients, 7 were first‐time ITI and 12 were rescue ITI. Of 7 first‐time patients, 6 had at least 1 high‐risk feature for ITI failure. Four of 7 first‐time patients were tolerized in a median of 7.8 months. The remaining 3 patients continue on rFVIIIFc ITI. Of 12 rescue patients, 7 initially achieved a negative Bethesda titre (≤0.6) in a median of 3.3 months, 1 had a decrease in Bethesda titre and continues on rFVIIIFc ITI and 4 have not demonstrated a decrease in Bethesda titre. Of these 4, 3 continue on rFVIIIFc ITI and 1 switched to bypass therapy alone. Two initially responsive patients transitioned to other factors due to recurrence. Overall, 16 of 19 patients remain on rFVIIIFc (prophylaxis or ITI). For those still undergoing ITI, longer follow‐up is needed to determine final outcomes. No adverse events reported. Conclusions Recombinant factor VIII Fc fusion protein demonstrated rapid time to tolerization in high‐risk first‐time ITI patients. For rescue ITI, rFVIIIFc showed therapeutic benefit in some patients who previously failed ITI with other products. These findings highlight the need to further evaluate the use of rFVIIIFc for ITI.