We report here that individuals with Noonan syndrome and juvenile myelomonocytic leukemia (JMML) have germline mutations in PTPN11 and that somatic mutations in PTPN11 account for 34% of non-syndromic JMML. Furthermore, we found mutations in PTPN11 in a small percentage of individuals with myelodysplastic syndrome (MDS) and de novo acute myeloid leukemia (AML). Functional analyses documented that the two most common mutations in PTPN11 associated with JMML caused a gain of function.

Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia

FOUR colony-stimulating factors influence the survival, proliferation, differentiation, and functional activation of myeloid hematopoietic cells: macrophage colony-stimulating factor (M-CSF), granulocyte colony-stimulating factor (G-CSF), granulocytemacrophage colony-stimulating factor (GM-CSF), and interleukin-3 (formerly known as multi-colony-stimulating factor).1 2 3 Various other cytokines and factors are also implicated in these processes, including interleukins 1, 5, 6, and 11 and the recently identified Steel factor (variously designated c-kit ligand, mast-cell growth factor, and stem-cell factor).4 , 5 Of these factors, only G-CSF and GM-CSF are commercially available for clinical use. G-CSF has been approved in the United States and major European countries for the reduction of infection after . . .

https://www.nejm.org/doi/pdf/10.1056/NEJM199207023270106?listPDF=true

Granulocyte Colony-Stimulating Factor and Granulocyte-Macrophage Colony-Stimulating Factor

The homing of hemopoietic stem cells to the bone marrow is mediated by specific interactions occurring between CXCR4, which is expressed on hemopoietic stem cells, and its ligand, stromal cell-derived factor-1 (SDF-1), a CXC chemokine secreted by bone marrow stromal cells. In the present study we evaluated the possibility that neuroblastoma cells use a mechanism similar to that used by hemopoietic stem cells to home to the bone marrow and adhere to bone marrow stromal cells. Our study suggests that CXCR4 expression may be a general characteristic of neuroblastoma cells. SH-SY5Y neuroblastoma cells express not only CXCR4, but also its ligand, SDF-1. CXCR4 expression on SH-SY5Y neuroblastoma cells is tightly regulated by tumor cell-derived SDF-1, as demonstrated by the ability of neutralizing Abs against human SDF-1alpha to up-regulate CXCR4 expression on the tumor cells. The reduction in CXCR4 expression following short term exposure to recombinant human SDF-1alpha can be recovered as a result of de novo receptor synthesis. Recombinant human SDF-1alpha induces the migration of CXCR4-expressing SH-SY5Y neuroblastoma cells in CXCR4- and heterotrimeric G protein-dependent manners. Furthermore, SH-SY5Y cells interact at multiple levels with bone marrow components, as evidenced by the fact that bone marrow-derived constituents promote SH-SY5Y cell migration, adhesion to bone marrow stromal cells, and proliferation. These results suggest that SH-SY5Y neuroblastoma cells are equipped with adequate machinery to support their homing to the bone marrow. Therefore, the ability of neuroblastoma tumors to preferentially form metastases in the bone marrow may be influenced by a set of complex CXCR4-SDF-1 interactions.

A Possible Role for CXCR4 and Its Ligand, the CXC Chemokine Stromal Cell-Derived Factor-1, in the Development of Bone Marrow Metastases in Neuroblastoma

Role of RUNX1 in hematological malignancies.

Germline mutations in PTPN11, the gene encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome (NS) and the clinically related LEOPARD syndrome (LS), whereas somatic mutations in the same gene contribute to leukemogenesis. On the basis of our previously gathered genetic and biochemical data, we proposed a model that splits NS- and leukemia-associated PTPN11 mutations into two major classes of activating lesions with differential perturbing effects on development and hematopoiesis. To test this model, we investigated further the diversity of germline and somatic PTPN11 mutations, delineated the association of those mutations with disease, characterized biochemically a panel of mutant SHP-2 proteins recurring in NS, LS, and leukemia, and performed molecular dynamics simulations to determine the structural effects of selected mutations. Our results document a strict correlation between the identity of the lesion and disease and demonstrate that NS-causative mutations have less potency for promoting SHP-2 gain of function than do leukemia-associated ones. Furthermore, we show that the recurrent LS-causing Y279C and T468M amino acid substitutions engender loss of SHP-2 catalytic activity, identifying a previously unrecognized behavior for this class of missense PTPN11 mutations.

Diversity and Functional Consequences of Germline and Somatic PTPN11 Mutations in Human Disease

Treatment of aplastic anemia in children with recombinant human granulocyte colony-stimulating factor.

Purpose This pilot study focussed on whether sequential molecular detection of minimal residual disease (MRD) in bone marrow (BM) could predict the outcome of patients with advanced neuroblastoma. Patients and Methods Bone marrow samples from 21 patients older than age 12 months with stage IV neuroblastoma were sequentially examined for tumor cell contamination by detecting tyrosine hydroxylase (TH) messenger ribonucleic acid (mRNA) using reverse transcription-polymerase chain reaction (RT-PCR). Twenty patients received myeloablative therapy with hematopoietic stem cell transplantation after achieving complete remission. Results All BM samples of patients except that of one patient was cytologically positive for neuroblastoma cells at diagnosis, and they became negative for neuroblastoma cells within 3 months by cytologic examination. By RT-PCR analysis, BM samples of all patients were positive for TH mRNA at diagnosis, and samples of 19 patients became negative for TH mRNA 1 to 13 months after the start of chemotherapy. Six patients whose BM samples became negative for TH mRNA within 4 months after the start of chemotherapy remained alive without evidence of disease (median 76 mos, range 36[ndash]91). In contrast, out of 15 patients whose BM samples remained positive, 10 patients had relapse develop and 9 patients died from disease (median 15 mos, range 10[ndash]25). There was a statistically significant difference in disease-free survival between the two groups (P [lt] 0.05). Conclusion Persistence of MRD in BM may predict poor prognosis in advanced neuroblastoma.

Disease outcome may be predicted by molecular detection of minimal residual disease in bone marrow in advanced neuroblastoma: a pilot study.

Spontaneous remission of juvenile chronic myelomonocytic leukemia in an infant with Noonan syndrome

Background
Childhood thrombocytopenias include immune thrombocytopenic purpura (ITP) and inherited thrombocytopenia; the former is caused by autoantibodies to platelets, whereas the latter can be distinguished by platelet size and underlying genetic mutations. Due to limited methods for the definite diagnosis of ITP, genetic and clinical parameters are required for diagnosing inherited thrombocytopenias with small or normal-sized platelets.

Procedure
In total, 32 Japanese patients with thrombocytopenia with small or normal-sized platelets from 29 families were enrolled. All the patients were under 20 years of age, with family histories of early-onset thrombocytopenia and/or poor response to conventional therapies for ITP. Genotypes and clinical parameters were retrospectively evaluated according to the disease type.

Results
Twelve cases of inherited thrombocytopenia were observed. We identified chromosomal deletions within the WASP gene in two patients with Wiskott–Aldrich syndrome; a missense mutation in a patient with X-linked thrombocytopenia; and mutations in the RUNX1 gene of five patients with familial platelet disorder with propensity to acute myelogenous leukemia, and in the ANKRD26 gene of four patients with autosomal dominant thrombocytopenia-2. All 12 carried germline mutations, three of which were de novo. Furthermore, we observed significantly elevated serum thrombopoietin (TPO) levels and dysplasia of megakaryocytes in patients carrying the RUNX1 and ANKRD26 mutations.

Conclusions
Genetic analyses and detection of TPO levels and dysmegakaryopoiesis were clinically useful for screening patients with inherited thrombocytopenias, irrespective of the family history. We hypothesize that the WASP, RUNX1, and ANKRD26 genes are important for normal TPO signaling and the network underlying thrombopoiesis. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.

Analyses of Genetic and Clinical Parameters for Screening Patients With Inherited Thrombocytopenia with Small or Normal-Sized Platelets.

PURPOSE We describe the case of a 9-year-old boy who developed Wernicke's encephalopathy while receiving chemotherapy for acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS After suffering anorexia for 4 weeks following chemotherapy, he exhibited nystagmus and ataxia. Symptoms rapidly worsened following an increased glucose load, and included a depressed consciousness, irregular respiration, and ophthalmoplegia. The serum thiamine level was 9 ng/ml (normal: 20-50). Cranial computed tomography (CT) revealed a low density area bilaterally at the neostriatum. Thiamine 100 mg/day was administered intravenously. RESULTS The patient's neurological signs improved dramatically. However, he subsequently developed pancytopenia and died of pneumonia. CONCLUSION The possibility of Wernicke's encephalopathy should be considered in children who are receiving chemotherapy for malignant disease when a persistent loss of appetite is followed by such neurological symptoms as nystagmus and ataxia.

Wernicke's encephalopathy in a child with acute lymphoblastic leukemia.

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