Development of an allele-specific minimal residual disease assay for patients with juvenile myelomonocytic leukemia. (1/36)

Juvenile myelomonocytic leukemia is an aggressive and frequently lethal myeloproliferative disorder of childhood. Somatic mutations in NRAS, KRAS, or PTPN11 occur in 60% of cases. Monitoring disease status is difficult because of the lack of characteristic leukemic blasts at diagnosis. We designed a fluorescently based, allele-specific polymerase chain reaction assay called TaqMAMA to detect the most common RAS or PTPN11 mutations. We analyzed peripheral blood and/or bone marrow of 25 patients for levels of mutant alleles over time. Analysis of pre-hematopoietic stem-cell transplantation, samples revealed a broad distribution of the quantity of the mutant alleles. After hematopoietic stem-cell transplantation, the level of the mutant allele rose rapidly in patients who relapsed and correlated well with falling donor chimerism. Simultaneously analyzed peripheral blood and bone marrow samples demonstrate that blood can be monitored for residual disease. Importantly, these assays provide a sensitive strategy to evaluate molecular responses to new therapeutic strategies.  (+info)

Role of mutation independent constitutive activation of FLT3 in juvenile myelomonocytic leukemia. (2/36)

FLT3 gene mutations have been identified as prognostic factors in myeloid malignancies. Furthermore, FLT3 can be activated by wild type overexpression or ligand-dependent in leukemic cells co-expressing FLT3 ligand (FLT3L). So far no data are available on FLT3/FLT3L expression and activation in JMML. In 51 clinical JMML samples, activating mutations were screened, FLT3 and FLT3L mRNA levels were assessed and the sensitivity of JMML cells to the FLT3 inhibitor PKC412 was tested by MTT assays. No evidence for constitutively activation of FLT3/FLT3L was found in JMML, indicating that FLT3 inhibitors are unlikely to be effective in JMML.  (+info)

Mutation analysis of the BRAF oncogene in juvenile myelomonocytic leukemia. (3/36)

Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative/myelodysplastic disorder associated with mutations in the Ras-Raf-MEK-ERK-signaling pathway. B-Raf plays a central role in this pathway. In 65 screened JMML patients we identified no BRAF mutations and we conclude that this gene is unlikely to play a role in the pathogenesis of JMML.  (+info)

Acquisition of loss of the wild-type NRAS locus with aggressive disease progression in a patient with juvenile myelomonocytic leukemia and a heterozygous NRAS mutation. (4/36)

In a patient with juvenile myelomonocytic leukemia, a NRAS mutation at codon 12 (GGT>TGT) was initially heterozygous, but became homozygous after blastic crisis (BC). According to microsatellite and FISH analyses, the post-BC homozygous mutation might result from the loss of the wild-type NRAS locus through mitotic recombination.  (+info)

Determination of Ras-GTP and Ras-GDP in patients with acute myelogenous leukemia (AML), myeloproliferative syndrome (MPS), juvenile myelomonocytic leukemia (JMML), acute lymphocytic leukemia (ALL), and malignant lymphoma: assessment of mutational and indirect activation. (5/36)

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Going with the flow: JAK-STAT signaling in JMML. (6/36)

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Single-cell profiling identifies aberrant STAT5 activation in myeloid malignancies with specific clinical and biologic correlates. (7/36)

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A retroviral mutagenesis screen reveals strong cooperation between Bcl11a overexpression and loss of the Nf1 tumor suppressor gene. (8/36)

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