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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Loss of neurofibromin or interferon consensus sequence binding protein (Icsbp) leads to a myeloproliferative disorder. Transcription of NF1 is directly controlled by ICSBP. It has been postulated that loss of NF1 expression resulting from loss of transcriptional activation by ICSBP contributes to human hematologic malignancies. To investigate the functional cooperation of these 2 proteins, we have established Icsbp-deficient mice with Nf1 haploinsufficiency. We here demonstrate that loss of Icsbp and Nf1 haploinsufficiency synergize to induce a forced myeloproliferation in Icsbp-deficient mice because of an expansion of a mature myeloid progenitor cell. Furthermore, Nf1 haploinsufficiency and loss of Icsbp contribute synergistically to progression of the myeloproliferative disorder toward transplantable leukemias. Leukemias are characterized by distinct phenotypes, which correlate with progressive genetic abnormalities. Loss of Nf1 heterozygosity is not mandatory for disease progression, but its occurrence with other genetic abnormalities indicates progressive genetic alterations in a defined subset of leukemias. These data show that loss of the 2 tumor suppressor genes Nf1 and Icsbp synergize in the induction of leukemias.
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PMID:Nf1 haploinsufficiency and Icsbp deficiency synergize in the development of leukemias. 1922 26

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.
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PMID:Juvenile myelomonocytic leukemia: epidemiology, etiopathogenesis, diagnosis, and management considerations. 2003 38

Neurofibromatosis type 1(NF1) is an autosomal dominant disorder with variable expression. The complications are age specific. Serious complication during early childhood is rare but optic glioma, brain tumors or leukemia may appear. Learning difficulties and attention deficit hyperactive disorders occur in as many as 60% of patients during school age. Overall, intelligence in neurofibromatosis is normal and mental retardation occurs in 6-7%. Managements for learning difficulties and attention deficit hyperactive disorders are especially important for quality of life in these patients. Skin neurofibromas or subcutaneous plexiform neurofibromas appear during childhood and may cause pain or spinal cord involvement. Malignant peripheral nerve sheath tumors that arise from plexiform neurifibromas are a particularly devastating complication during middle age.
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PMID:[Continuous clinical management of patients with neurofibromatosis type 1]. 2007 5

Mutations in NF1, PTPN11, NRAS, KRAS and CBL have been reported to play a pathogenetic role in juvenile myelomonocytic leukaemia (JMML), a rare myelodyplastic/myeloproliferative neoplasm occurring in children. Recently, mutations in ASXL1 were identified in chronic myelomonocytic leukaemia and other myeloid malignancies. We sequenced exon 12 of ASLX1 in 49 JMML patients, and found 2 novel heterozygous (nonsense and frameshift) mutations, one occurring as a sole lesion, the other was in conjunction with a PTPN11 mutation. ASXL1 cooperates with KDM1A in transcriptional repression and thereby ASXL1 mutations may synergize with or mimic other JMML-related mutations.
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PMID:Spectrum of molecular defects in juvenile myelomonocytic leukaemia includes ASXL1 mutations. 2040 41

Leukemias including acute myeloid leukemia (AML), acute lymphocytic leukemia, and chronic myeloid leukemia as well as myelodysplastic syndrome (MDS), male non-Hodgkin lymphoma and MGUS are statistically significant radiation-associated hematopoietic neoplasms. Recently, MDS has been confirmed to increase among atomic bomb survivors. AML/RUNX1 is a critical transcription factor of differentiation and proliferation of hematopoietic stem cells. AML1 point mutations, especially N-terminal RUNT domain in-frame type, are frequently detected in radiaton-associated and therapy-related (rad-t-) MDS/AML. In addition, the point mutations, are frequently associated with additional mutations in receptor tyrosine kinase (RTK)-RAS pathway, including FLT3, N-RAS, SHP2 and NF1. The combination of AML1/RUNX1 mutation and RTK-RAS pathway mutation in hematopoietic stem cells is considered responsible for the oncogenesis of rad-t- MDS/AML.
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PMID:[Radiation associated leukemia and myelodysplastic syndrome]. 2251 21

Juvenile myelomonocytic leukemia (JMML) is an intractable pediatric leukemia with poor prognosis whose molecular pathogenesis is poorly understood, except for somatic or germline mutations of RAS pathway genes, including PTPN11, NF1, NRAS, KRAS and CBL, in the majority of cases. To obtain a complete registry of gene mutations in JMML, whole-exome sequencing was performed for paired tumor-normal DNA from 13 individuals with JMML (cases), which was followed by deep sequencing of 8 target genes in 92 tumor samples. JMML was characterized by a paucity of gene mutations (0.85 non-silent mutations per sample) with somatic or germline RAS pathway involvement in 82 cases (89%). The SETBP1 and JAK3 genes were among common targets for secondary mutations. Mutations in the latter were often subclonal and may be involved in the progression rather than the initiation of leukemia, and these mutations associated with poor clinical outcome. Our findings provide new insights into the pathogenesis and progression of JMML.
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PMID:Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia. 2389 62

We report a case of a 65-year old patient affected by neurofibromatosis 1, documented by the presence of germ-line mutation on the NF1 gene, who developed various hyperproliferative malignant and benign diseases. He was brought to our attention for the diagnosis of acute myeloid leukemia revealed by major fatigue and dyspnea. The disease characteristics at diagnosis were hyperleukocytosis and complex karyotype with the inversion of the chromosome 16, classifying as a high-risk leukemia. The association between leukemia and neurofibromatosis 1 is controversial and needs to be further investigated. Nevertheless, such patients present a wide number of comorbidities that make therapeutic strategies most difficult.
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PMID:A case report of acute myeloid leukemia and neurofibromatosis 1. 2388 44

Juvenile myelomonocytic leukemia (JMML) is a unique, aggressive hematopoietic disorder of infancy/early childhood caused by excessive proliferation of cells of monocytic and granulocytic lineages. Approximately 90% of patients carry either somatic or germline mutations of PTPN-11, K-RAS, N-RAS, CBL, or NF1 in their leukemic cells. These genetic aberrations are largely mutually exclusive and activate the Ras/mitogen-activated protein kinase pathway. Allogeneic hematopoietic stem cell transplantation (HSCT) remains the therapy of choice for most patients with JMML, curing more than 50% of affected children. We recommend that this option be promptly offered to any child with PTPN-11-, K-RAS-, or NF1-mutated JMML and to the majority of those with N-RAS mutations. Because children with CBL mutations and few of those with N-RAS mutations may have spontaneous resolution of hematologic abnormalities, the decision to proceed to transplantation in these patients must be weighed carefully. Disease recurrence remains the main cause of treatment failure after HSCT. A second allograft is recommended if overt JMML relapse occurs after transplantation. Recently, azacytidine, a hypomethylating agent, was reported to induce hematologic/molecular remissions in some children with JMML, and its role in both reducing leukemia burden before HSCT and in nontransplant settings requires further studies.
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PMID:How I treat juvenile myelomonocytic leukemia. 2556 99

The objective of the study was to compare executive functioning (EF) profiles across several pediatric medical conditions and explore the influence of age of diagnosis and evaluation. A retrospective, cross-sectional study of 734 children aged 5 to 18 years was conducted across five medical groups (brain tumor, leukemia [ALL], epilepsy [EPI], neurofibromatosis type 1 [NF1], and ornithine transcarbamylase deficiency [OTC-D]), attention deficit hyperactivity disorder (ADHD) controls, and matched healthy controls. We compared groups across the scales of a parent-completed Behavior Rating Inventory of Executive Functioning (BRIEF) using a repeated measures analysis of variance (ANOVA). Separate ANOVAs were conducted to look at age factors. The results showed that the ADHD group differed from all other groups and had the highest level of reported EF problems. The NF1 and OTC-D groups differed significantly from the healthy comparison group for overall EF problems, while the EPI and cancer groups did not. Working memory was the most elevated scale across medical groups, followed by plan/organize. Children with medical disorders were two to four times more likely than healthy controls to have clinically significant problems in several EF domains. There was a main effect for age at diagnosis and age at evaluation. A subset of children with medical disorders were found to have parent-reported EF difficulties, with particular vulnerability noted in working memory and organizational/planning skills. This has relevance for the development of interventions that may be helpful across disorders. Children with particular diagnoses and earlier age of diagnosis and evaluation had greater reported EF problems.
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PMID:Executive functioning profiles from the BRIEF across pediatric medical disorders: Age and diagnosis factors. 2614 38

Chronic and juvenile myelomonocytic leukemias (CMML and JMML) are myelodysplastic/myeloproliferative neoplasia (MDS/MPN) overlap syndromes that respond poorly to conventional treatments. Aberrant Ras activation because of NRAS, KRAS, PTPN11, CBL and NF1 mutations is common in CMML and JMML. However, no mechanism-based treatments currently exist for cancers with any of these mutations. An alternative therapeutic strategy involves targeting Ras-regulated effector pathways that are aberrantly activated in CMML and JMML, which include the Raf/MEK/ERK and phosphoinositide-3'-OH kinase (PI3K)/Akt cascades. Mx1-Cre, Kras(D12) and Mx1-Cre, Nf1(flox/)(-) mice accurately model many aspects of CMML and JMML. Treating Mx1-Cre, Kras(D12) mice with GDC-0941 (also referred to as pictilisib), an orally bioavailable inhibitor of class I PI3K isoforms, reduced leukocytosis, anemia and splenomegaly while extending survival. However, GDC-0941 treatment attenuated activation of both PI3K/Akt and Raf/MEK/ERK pathways in primary hematopoietic cells, suggesting it could be acting through suppression of Raf/MEK/ERK signals. To interrogate the importance of the PI3K/Akt pathway specifically, we treated mice with the allosteric Akt inhibitor MK-2206. This compound had no effect on Raf/MEK/ERK signaling, yet it also induced robust hematologic responses in Kras and Nf1 mice with MPN. These data support investigating PI3K/Akt pathway inhibitors as a therapeutic strategy in JMML and CMML patients.
Leukemia 2016 06
PMID:Targeting the PI3K/Akt pathway in murine MDS/MPN driven by hyperactive Ras. 2696 85


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