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Systematic screen for tyrosine kinase rearrangements identifies a novel C6orf204-PDGFRB fusion in a patient with recurrent T-ALL and an associated myeloproliferative neoplasm.
Chmielecki J, Peifer M, Viale A, Hutchinson K, Giltnane J, Socci ND, Hollis CJ, Dean RS, Yenamandra A, Jagasia M, Kim AS, Davé UP, Thomas RK, Pao W
(2012) Genes Chromosomes Cancer 51: 54-65
MeSH Terms: Adult, Algorithms, Amino Acid Sequence, Base Sequence, Cell Line, Tumor, Computational Biology, Cytoskeletal Proteins, Gene Order, HEK293 Cells, Humans, K562 Cells, Karyotyping, Male, Molecular Sequence Data, Myeloproliferative Disorders, Oncogene Proteins, Fusion, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Protein-Tyrosine Kinases, Sequence Alignment, Sequence Analysis, DNA, Translocation, Genetic
Show Abstract · Added September 3, 2013
Gene fusions involving the catalytic domain of tyrosine kinases (TKs) are found in a variety of hematological and solid tumor malignancies. Clinically, TK fusions have emerged as prime targets for therapy with small molecule kinase inhibitors. Unfortunately, identification of TK fusions has been hampered by experimental limitations. Here, we developed version 2.0 of a genomically based systematic kinase fusion screen and used it to detect a novel imatinib-sensitive C6orf204-PDGFRB fusion in a patient with precursor T lymphoblastic lymphoma (T-ALL) and an associated myeloproliferative neoplasm with eosinophilia. These data validate the ability of this targeted capture-sequencing approach to detect TK fusion events in small amounts of DNA extracted directly from patient samples.
Copyright © 2011 Wiley Periodicals, Inc.
0 Communities
4 Members
0 Resources
21 MeSH Terms
Single-cell profiling identifies aberrant STAT5 activation in myeloid malignancies with specific clinical and biologic correlates.
Kotecha N, Flores NJ, Irish JM, Simonds EF, Sakai DS, Archambeault S, Diaz-Flores E, Coram M, Shannon KM, Nolan GP, Loh ML
(2008) Cancer Cell 14: 335-43
MeSH Terms: Adult, Biomarkers, Tumor, Cell Proliferation, Cells, Cultured, Child, Disease Progression, Flow Cytometry, Gene Expression Regulation, Neoplastic, Granulocyte-Macrophage Colony-Stimulating Factor, Humans, Janus Kinase 2, Leukemia, Myelomonocytic, Juvenile, Myeloproliferative Disorders, Neoplasm Staging, Phosphorylation, Recurrence, STAT5 Transcription Factor, Signal Transduction, Treatment Outcome
Show Abstract · Added February 15, 2013
Progress in understanding the molecular pathogenesis of human myeloproliferative disorders (MPDs) has led to guidelines incorporating genetic assays with histopathology during diagnosis. Advances in flow cytometry have made it possible to simultaneously measure cell type and signaling abnormalities arising as a consequence of genetic pathologies. Using flow cytometry, we observed a specific evoked STAT5 signaling signature in a subset of samples from patients suspected of having juvenile myelomonocytic leukemia (JMML), an aggressive MPD with a challenging clinical presentation during active disease. This signature was a specific feature involving JAK-STAT signaling, suggesting a critical role of this pathway in the biological mechanism of this disorder and indicating potential targets for future therapies.
1 Communities
1 Members
0 Resources
19 MeSH Terms
K-RasG12D expression induces hyperproliferation and aberrant signaling in primary hematopoietic stem/progenitor cells.
Van Meter ME, Díaz-Flores E, Archard JA, Passegué E, Irish JM, Kotecha N, Nolan GP, Shannon K, Braun BS
(2007) Blood 109: 3945-52
MeSH Terms: Animals, Cell Proliferation, Extracellular Signal-Regulated MAP Kinases, Granulocyte-Macrophage Colony-Stimulating Factor, Hematopoietic Stem Cells, Mice, Mice, Transgenic, Myeloproliferative Disorders, Neoplastic Stem Cells, Point Mutation, Proto-Oncogene Proteins p21(ras), Ribosomal Protein S6 Kinases, STAT5 Transcription Factor, Signal Transduction
Show Abstract · Added February 15, 2013
Defining how cancer-associated mutations perturb signaling networks in stem/progenitor populations that are integral to tumor formation and maintenance is a fundamental problem with biologic and clinical implications. Point mutations in RAS genes contribute to many cancers, including myeloid malignancies. We investigated the effects of an oncogenic Kras(G12D) allele on phosphorylated signaling molecules in primary c-kit(+) lin(-/low) hematopoietic stem/progenitor cells. Comparison of wild-type and Kras(G12D) c-kit(+) lin(-/low) cells shows that K-Ras(G12D) expression causes hyperproliferation in vivo and results in abnormal levels of phosphorylated STAT5, ERK, and S6 under basal and stimulated conditions. Whereas Kras(G12D) cells demonstrate hyperactive signaling after exposure to granulocyte-macrophage colony-stimulating factor, we unexpectedly observe a paradoxical attenuation of ERK and S6 phosphorylation in response to stem cell factor. These studies provide direct biochemical evidence that cancer stem/progenitor cells remodel signaling networks in response to oncogenic stress and demonstrate that multi-parameter flow cytometry can be used to monitor the effects of targeted therapeutics in vivo. This strategy has broad implications for defining the architecture of signaling networks in primary cancer cells and for implementing stem cell-targeted interventions.
1 Communities
1 Members
0 Resources
14 MeSH Terms
Conditional MLL-CBP targets GMP and models therapy-related myeloproliferative disease.
Wang J, Iwasaki H, Krivtsov A, Febbo PG, Thorner AR, Ernst P, Anastasiadou E, Kutok JL, Kogan SC, Zinkel SS, Fisher JK, Hess JL, Golub TR, Armstrong SA, Akashi K, Korsmeyer SJ
(2005) EMBO J 24: 368-81
MeSH Terms: Animals, CREB-Binding Protein, DNA-Binding Proteins, Histone-Lysine N-Methyltransferase, Mice, Molecular Sequence Data, Myeloid-Lymphoid Leukemia Protein, Myeloproliferative Disorders, Nuclear Proteins, Proto-Oncogenes, Reverse Transcriptase Polymerase Chain Reaction, Trans-Activators, Transcription Factors
Show Abstract · Added April 7, 2010
Chromosomal translocations that fuse the mixed lineage leukemia (MLL) gene with multiple partners typify acute leukemias of infancy as well as therapy-related leukemias. We utilized a conditional knockin strategy to bypass the embryonic lethality caused by MLL-CBP expression and to assess the immediate effects of induced MLL-CBP expression on hematopoiesis. Within days of activating MLL-CBP, the fusion protein selectively expanded granulocyte/macrophage progenitors (GMP) and enhanced their self-renewal/proliferation. MLL-CBP altered the gene expression program of GMP, upregulating a subset of genes including Hox a9. Inhibition of Hox a9 expression by RNA interference demonstrated that MLL-CBP required Hox a9 for its enhanced cell expansion. Following exposure to sublethal gamma-irradiation or N-ethyl-N-nitrosourea (ENU), MLL-CBP mice developed myelomonocytic hyperplasia and progressed to fatal myeloproliferative disorders. These represented the spectrum of therapy-induced acute myelomonocytic leukemia/chronic myelomonocytic leukemia/myelodysplastic/myeloproliferative disorder similar to that seen in humans possessing the t(11;16). This model of MLL-CBP therapy-related myeloproliferative disease demonstrates the selectivity of this MLL fusion for GMP cells and its ability to initiate leukemogenesis in conjunction with cooperating mutations.
0 Communities
1 Members
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13 MeSH Terms
Proapoptotic BID is required for myeloid homeostasis and tumor suppression.
Zinkel SS, Ong CC, Ferguson DO, Iwasaki H, Akashi K, Bronson RT, Kutok JL, Alt FW, Korsmeyer SJ
(2003) Genes Dev 17: 229-39
MeSH Terms: Animals, Apoptosis, BH3 Interacting Domain Death Agonist Protein, Carrier Proteins, Chromosome Aberrations, Female, Homeostasis, Leukemia, Myelomonocytic, Chronic, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Myelopoiesis, Myeloproliferative Disorders, Signal Transduction
Show Abstract · Added September 7, 2011
The proper expansion and contraction of hematopoietic cells requires tight regulation of cell death. BID, a "BH3-only" molecule, amplifies death receptor signals connecting the extrinsic to intrinsic pathways by triggering the mitochondrial pathway of apoptosis. Bid-deficient mice, as they age, spontaneously develop a myeloproliferative disorder, which progresses from myeloid hyperplasia to a fatal, clonal malignancy closely resembling chronic myelomonocytic leukemia (CMML). Thus, an apoptotic defect can result in myeloid leukemogenesis. Premalignant Bid-/- myeloid precursor cells are resistant to death receptor-induced apoptosis. Furthermore, a competitive reconstitution assay demonstrates that Bid-deficient long-term repopulating cells give rise to expanded myelomonocytic cells in vivo. Surprisingly, a single BH3-only molecule operating in the extrinsic death receptor pathway proved essential in vivo for physiologic cell death required to maintain myeloid homeostasis. Moreover, progression to CMML indicates that an upstream BH3-only molecule, BID, is required to suppress tumorigenesis.
1 Communities
1 Members
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15 MeSH Terms