Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Infants with leukemia who require hematopoietic cell transplantation (HCT) remain 1 of the most significant challenges in pediatric stem cell transplant. Infant leukemia is characterized by a unique biology including a predominance mixed lineage leukemia(MLL) gene rearrangement and juvenile myelomonocytic leukemia. Moreover, the long-term effects of transplantation are particularly prominent in infants who have active endocrine, cardiovascular, pulmonary, neurologic, musculoskeletal, hearing, and vision development, with the added risk of second malignant neoplasms. Currently, there is no solid basis to support allogeneic HCT as first-line therapy for infant acute lymphoblastic leukemia-first remission (ALL-CR1), although indicated for other infant leukemias, including juvenile myelomonocytic leukemia (JMML). The relative long-term toxicity of total body irridiation (TBI) versus non-TBI containing preparative regimens for HCT in infants remains controversial, with the differences, especially on neurocognitive function, unknown.
 ...
PMID:Controversies of and unique issues in hematopoietic cell transplantation for infant leukemia. 1914 83

PTPN11, which encodes the tyrosine phosphatase SHP2, is mutated in approximately 35% of patients with juvenile myelomonocytic leukemia (JMML) and at a lower incidence in other neoplasms. To model JMML pathogenesis, we generated knockin mice that conditionally express the leukemia-associated mutant Ptpn11(D61Y). Expression of Ptpn11(D61Y) in all hematopoietic cells evokes a fatal myeloproliferative disorder (MPD), featuring leukocytosis, anemia, hepatosplenomegaly, and factor-independent colony formation by bone marrow (BM) and spleen cells. The Lin(-)Sca1(+)cKit(+) (LSK) compartment is expanded and "right-shifted," accompanied by increased stem cell factor (SCF)-evoked colony formation and Erk and Akt activation. However, repopulating activity is decreased in diseased mice, and mice that do engraft with Ptpn11(D61Y) stem cells fail to develop MPD. Ptpn11(D61Y) common myeloid progenitors (CMPs) and granulocyte-monocyte progenitors (GMPs) produce cytokine-independent colonies in a cell-autonomous manner and demonstrate elevated Erk and Stat5 activation in response to granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulation. Ptpn11(D61Y) megakaryocyte-erythrocyte progenitors (MEPs) yield increased numbers of erythrocyte burst-forming units (BFU-Es), but MEPs and erythrocyte-committed progenitors (EPs) produce fewer erythrocyte colony-forming units (CFU-Es), indicating defective erythroid differentiation. Our studies provide a mouse model for Ptpn11-evoked MPD and show that this disease results from cell-autonomous and distinct lineage-specific effects of mutant Ptpn11 on multiple stages of hematopoiesis.
 ...
PMID:Leukemogenic Ptpn11 causes fatal myeloproliferative disorder via cell-autonomous effects on multiple stages of hematopoiesis. 1917 68

SHP-2 is a cytoplasmic protein tyrosine phosphatase (PTP) that contains two Src homology 2 (SH2) domains. Although PTPs are generally considered to be negative regulators on the basis of their ability to oppose the effects of protein tyrosine kinases, SHP-2 is unusual in that it promotes the activation of the Ras-MAPK signaling pathway by receptors for various growth factors and cytokines. The molecular basis for the activation of SHP-2 is also unique: In the basal state, the NH(2)-terminal SH2 domain of SHP-2 interacts with the PTP domain, resulting in autoinhibition of PTP activity; the binding of SHP-2 via its SH2 domains to tyrosine-phosphorylated growth factor receptors or docking proteins, however, results in disruption of this intramolecular interaction, leading to exposure of the PTP domain and catalytic activation. Indeed, SHP-2 proteins with artificial mutations in the NH(2)-terminal SH2 domain have been shown to act as dominant active mutants in vitro. Such activating mutations of PTPN11 (human SHP-2 gene) were subsequently identified in individuals with Noonan syndrome, a human developmental disorder that is sometimes associated with juvenile myelomonocytic leukemia. Furthermore, somatic mutations of PTPN11 were found to be associated with pediatric leukemia. SHP-2 is also thought to participate in the development of other malignant disorders, but in a manner independent of such activating mutations. Biochemical and functional studies of SHP-2 and genetic analysis of PTPN11 in human disorders have thus converged to provide new insight into the pathogenesis of cancer as well as potential new targets for cancer treatment.
 ...
PMID:Protein tyrosine phosphatase SHP-2: a proto-oncogene product that promotes Ras activation. 1962 5

The aim of this study was to describe the characteristics and outcome in a group of pediatric patients with hematological malignancies who developed hemophagocytosis at diagnosis or during the disease course. Eight patients with hematological malignancy and associated hemophagocytosis were included. The initial diagnosis was juvenile myelomonocytic leukemia (JMML) in five, nonlymphoblastic leukemia (ANLL) in two, and T-cell lymphoma associated with myeloproliferative syndrome in one patient. Hemophagocytosis was concomitantly present at the time of diagnosis of the primary disease in four of the five patients with JMML and in the two patients with ANLL. Three had abnormalities related to chromosome 8 [(trisomy 8, monosomy 8, and t (8;13) (p11; p12)], and one had inversion 16. Multiple chromosomal losses were present in one patient, including both chromosomes 8 and 16. Bone marrow karyotyping revealed 46, XX; 47, XXX mosaicism in one patient. Two patients had PTPN11 mutation and one patient k-RAS mutation. The patients with JMML and neurofibromatosis (n = 2), the patient with lymphoma and t (8;13) positive AML, and a fourth patient with PTPN11 mutation did not remit and had unfavorable outcomes.
 ...
PMID:Hemophagocytosis associated with leukemia: a striking association with juvenile myelomonocytic leukemia. 1979 2

The development of xanthogranulomas has been linked to hematologic malignancies in children and adults, based on a number of reports in the literature. In children, a specific association between juvenile xanthogranuloma, neurofibromatosis 1, and juvenile myelomonocytic leukemia has been described. We report a case of a 9-month-old child, without a known diagnosis of neurofibromatosis 1, who presented with hepatosplenomegaly, anemia, thrombocytopenia, and multiple cutaneous nodules, which were confirmed to be juvenile xanthogranulomas upon biopsy. A concurrent work-up showed that the child had juvenile myelomonocytic leukemia. Although cutaneous juvenile xanthogranulomas are benign lesions, in several reported cases they have been shown to herald leukemia. This association between xanthogranulomas and hematologic malignancy is poorly understood. Juvenile xanthogranulomas have a number of morphologic variants and clinical presentations that can be confused with the cutaneous lesions of Langerhans cell histiocytosis and dermatofibroma. Recognition of the broad clinicopathologic spectrum of juvenile xanthogranulomas is critical for proper diagnosis.
 ...
PMID:Cutaneous xanthogranulomas, hepatosplenomegaly, anemia, and thrombocytopenia as presenting signs of juvenile myelomonocytic leukemia. 2000 Aug 79

The overall risk of cancer in children with Noonan (NS), cardio-facial-cutaneous, Costello or LEOPARD syndrome is high, although no precise estimates are available. There are few data on cancer in adults with NS, but the reported numbers of malignancies in adults do not seem excessive. Juvenile myelomonocytic leukemia (JMML) is a rare aggressive leukemia in young children. A JMML-like myeloproliferative disorder has been described in about 30 neonates with NS and the PTPN11 mutation. The disorder often regresses spontaneously, but fatal complications may occur. A review of the literature indicates an increased risk of acute lymphoblastic leukemia and acute myeloid leukemia in NS. Young children with Costello syndrome have an extremely high risk of rhabdomyosarcoma, and also an increased risk of neuroblastoma and bladder carcinoma. Registry-based studies of patients with NS and related disorders diagnosed with molecular genetics and a high-quality long-term follow-up are necessary to further estimate the incidence of malignancy.
 ...
PMID:Malignant diseases in Noonan syndrome and related disorders. 2002 31

Juvenile myelomonocytic leukemia (JMML) is a rare hematopoietic malignancy of early childhood with features characteristic of both myelodysplastic and myeloproliferative disorders. Recent studies clearly show that the deregulated activation of the RAS signaling pathway plays a central role in the pathogenesis of JMML. 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. Patients with JMML respond poorly to chemotherapy, and the probability of survival without allogeneic hematopoietic stem cell transplantation (HSCT) is less than 10%. Recent studies show that the event-free survival after HSCT is between 24 and 54%, with no difference between transplants using matched family donors and those using unrelated donors. The use of therapies such as intensive chemotherapy and splenectomy prior to HSCT does not improve the outcome. The relapse rate following HSCT is over 30%, which is unacceptably high. Cumulative evidence suggests that a graft-versus-leukemia effect occurs in JMML. Donor leukocyte infusion is not usually successful in JMML, but the outcome of second HSCT is generally favorable. Based on recent advances in the understanding of the pathogenesis of JMML, the development of novel targeted therapies, which might improve the outcome of patients, is keenly awaited.
 ...
PMID:Juvenile myelomonocytic leukemia: epidemiology, etiopathogenesis, diagnosis, and management considerations. 2003 38

PURPOSE Juvenile myelomonocytic leukemia (JMML) is a rare early childhood myelodysplastic/myeloproliferative disorder characterized by an aggressive clinical course. Age and hemoglobin F percentage at diagnosis have been reported to predict both survival and outcome after hematopoietic stem cell transplantation (HSCT). However, no genetic markers with prognostic relevance have been identified so far. We applied gene expression-based classification to JMML samples in order to identify prognostic categories related to clinical outcome. PATIENTS AND METHODS Samples of 44 patients with JMML were available for microarray gene expression analysis. A diagnostic classification (DC) model developed for leukemia and myelodysplastic syndrome classification was used to classify the specimens and identify prognostically relevant categories. Statistical analysis was performed to determine the prognostic value of the classification and the genes identifying prognostic categories were further analyzed through R software. RESULTS The samples could be divided into two major groups: 20 specimens were classified as acute myeloid leukemia (AML) -like and 20 samples as nonAML-like. Four patients could not be assigned to a unique class. The 10-year probability of survival after diagnosis of AML-like and nonAML-like patients was significantly different (7% v 74%; P = .0005). Similarly, the 10-year event-free survival after HSCT was 6% for AML-like and 63% for nonAML-like patients (P = .0010). CONCLUSION Gene expression-based classification identifies two groups of patients with JMML with distinct prognosis outperforming all known clinical parameters in terms of prognostic relevance. Gene expression-based classification could thus be prospectively used to guide clinical/therapeutic decisions.
 ...
PMID:Gene expression-based classification as an independent predictor of clinical outcome in juvenile myelomonocytic leukemia. 2023 85

Deregulation of signaling pathways, through mutation or other molecular changes, can ultimately result in disease. The tyrosine phosphatase Shp2 has emerged as a major regulator of receptor tyrosine kinase (RTK) and cytokine receptor signaling. In the last decade, germline mutations in the human PTPN11 gene, encoding Shp2, were linked to Noonan (NS) and LEOPARD syndromes, two multisymptomatic developmental disorders that are characterized by short stature, craniofacial defects, cardiac defects, and mental retardation. Somatic Shp2 mutations are also associated with several types of human malignancies, such as the most common juvenile leukemia, juvenile myelomonocytic leukemia (JMML). Whereas NS and JMML are caused by gain-of-function (GOF) mutations of Shp2, loss-of-function (LOF) mutations are thought to be associated with LEOPARD syndrome. Animal models that carry conditional LOF and GOF mutations have allowed a better understanding of the mechanism of Shp2 function in disease, and shed light on the role of Shp2 in signaling pathways that control decisive events during embryonic development or during cellular transformation/tumorigenesis.
 ...
PMID:The tyrosine phosphatase Shp2 in development and cancer. 2039 56

Juvenile myelomonocytic leukaemia (JMML), previously known as juvenile chronic myeloid leukaemia (JCML) is a rare, myelodysplastic - myeloproliferative disease typically presenting in early childhood. This disorder is difficult to distinguish from other myeloproliferative syndrome such as chronic myeloid leukaemia (CML) because of the similarities in their clinical and bone marrow findings. However, because of its unique biological characteristics such as absolute monocytosis with dysplasia, absence of Philadelphia chromosome or BCR-ABL fusion protein, hypergammaglobulinaemia and raised fetal haemoglobin level, this disorder does not satisfy the criteria for inclusion in the CML or chronic myelomonocytic leukaemia (CMML) group, as seen in adult patients. We describe a series of three patients with JMML, who had almost similar clinical and laboratory findings, and discuss the difficulty in the classification and treatment of the disease.
 ...
PMID:Juvenile myelomonocytic leukaemia: a case series. 2051 55


<< Previous 1 2 3 4 5 6 7 8 9 10