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Biomedical subjects

Kevin M Shannon

Publications and source records attributed to Kevin M Shannon.

27 records · Page 2Linked to original sources
PubMed2002

Hematologic effects of inactivating the Ras processing enzyme Rce1.

Posttranslational processing of Ras proteins has attracted considerable interest as a potential target for anticancer drug discovery. Rce1 encodes an endoprotease that facilitates membrane targeting of Ras and other prenylated proteins by releasing the carboxyl-terminal 3 amino acids (ie, the -AAX of the CAAX motif). Homozygous Rce1 mutant embryos (Rce1(-/-)) die late in gestation. To characterize the role of Rce1 in hematopoiesis, we performed adoptive transfers and investigated cells from the recipients. Rce1(-/-) fetal liver cells rescued lethally irradiated recipients and manifested normal long-term repopulating potential in competitive repopulation assays. The recipients of Rce1(-/-) cells developed modest elevations in mature myeloid cells (neutrophils + monocytes), but remained well. Bone marrow cells from mice that received transplants of Rce1(-/-) activated extracellular signal-related kinase (ERK) normally in response to granulocyte-macrophage colony-stimulating factor. These data suggest that pharmacologic inhibitors of Rce1 will have minimal effects on normal hematopoietic cells.

Adoptive Transfer↗
PubMed2002

MLL5, a homolog of Drosophila trithorax located within a segment of chromosome band 7q22 implicated in myeloid leukemia.

Proteins encoded by Polycomb and Trithorax-group (Pc-G and Trx-G) genes regulate developmental fates by maintaining or repressing HOX gene expression, respectively. In a search for candidate myeloid leukemia tumor suppressor genes from a approximately 2.5 Mb commonly-deleted segment within chromosome band 7q22, we identified a novel human Trithorax (Trx) family member named MLL5. Trx-G genes encode proteins that modulate transcriptional programs through protein-protein interactions that are mediated by PHD and SET domains, and by binding to DNA via A-T hooks and methyltransferase homology motifs. MLL5 is a homolog of the Drosophila gene CG9007; it encodes a 6.5 kb mRNA that is expressed widely. MLL5 includes a SET domain and a single PHD finger, but lacks A-T hooks and methyltransferase homology domains that are found in MLL. The leukemia cell line RCV-ACV-A carries a heterozygous missense mutation within the PHD domain; however, no mutations within the MLL5 coding region were detected in primary leukemias. MLL5 is a novel mammalian Trx-G gene that might modulate transcription by protein association.

Amino Acid Sequence↗
PubMed2002

Genomic structure of the PIK3CG gene on chromosome band 7q22 and evaluation as a candidate myeloid tumor suppressor.

PIK3CG, which encodes the catalytic subunit p110 gamma of phosphoinositide 3-OH-kinase-gamma (PI3K gamma), has been assigned to chromosome band 7q22, a region that is frequently deleted in myeloid malignancies. PI3K gamma-mutant mice have hematologic defects and are predisposed to colon cancer. On the basis of these data, PIK3CG was evaluated as a candidate myeloid tumor suppressor gene (TSG). PIK3CG was mapped by fluorescence in situ hybridization adjacent and telomeric to a commonly deleted segment defined previously in myeloid leukemias with breakpoints within 7q22. PIK3CG contains 10 exons and spans approximately 37 kilobases of genomic DNA. Forty leukemias with monosomy 7 or a del(7q) were screened for PIK3CG mutations. Two patients had missense variations affecting residue 859 in the N-terminal catalytic domain of the protein. This allele was also detected in unaffected parents and in 1 of 60 control alleles; it probably represents a polymorphism. PIK3CG is unlikely to act as a recessive TSG in myeloid leukemias with monosomy 7.

Chromosome Mapping↗
PubMed2002

Resistance in the land of molecular cancer therapeutics.

The fusion tyrosine kinase Bcr-Abl plays a fundamental role in the pathogenesis of chronic myeloid leukemia (CML). Imatinib, a potent inhibitor of Bcr-Abl, has shown impressive clinical activity in CML patients. However, primary and acquired resistance occurs in many patients and is associated with reactivation of Bcr-Abl in primary leukemia cells. Studies reported over the past year have begun to elucidate the molecular basis of imatinib resistance, which may involve amplification of BCR-ABL or, more commonly, mutations that introduce amino acid substitutions into the Bcr-Abl kinase. Biochemical analysis and molecular modeling indicate that these mutant proteins retain kinase activity but are less sensitive to inhibition due to structural changes that perturb drug binding. These studies establish a paradigm for elucidating resistance to targeted therapeutics.

Antineoplastic Agents↗
PubMed2002

Acute leukemia: a pediatric perspective.

The spectrum of hematological malignancies differs markedly between children and adults. Moreover, diseases such as acute lymphoblastic leukemia, acute myeloid leukemia, and myelodysplastic syndrome also demonstrate distinct biologic features and responses to treatment between these populations. In this review, we summarize our current understanding of the molecular pathology of acute leukemia and myelodysplastic syndrome, emphasizing areas in which studies in pediatric patients are providing unique insights into the hematopoietic malignancies of adults.

Adult↗
PubMed2002

Hyperactivation of protein kinase B and ERK have discrete effects on survival, proliferation, and cytokine expression in Nf1-deficient myeloid cells.

The Nf1 tumor suppressor encodes a GTPase-activating protein for Ras. Previous work has implicated hyperactive Ras in the aberrant growth of Nf1-deficient cells; however, there are limited data on which effectors modulate specific phenotypes. To address this, we generated myeloid cell lines by infecting fetal liver cells with a retrovirus encoding a truncated allele of c-Myb. Granulocyte-macrophage colony stimulating factor (GM-CSF) promoted the survival of wild-type Myb cells in a dose-dependent manner. By contrast, Nf1-deficient myeloid cells deprived of growth factors, were resistant to apoptosis due to hyperactivation of the phosphoinositide-3-OH kinase/protein kinase B cascade. Nf1(-/-) cells also demonstrated growth factor-independent proliferation and upregulation of GM-CSF mRNA production that were dependent upon Raf/MEK/ERK signaling. These data link specific Ras effectors with discrete cellular phenotypes in Nf1-deficient cells.

Animals↗
PubMed2002

Use of implantable cardioverter-defibrillators in pediatric patients.

Automatic implantable cardioverter-defibrillator use has become widespread in the prevention of sudden death in at-risk populations. The compelling safety and efficacy data in numerous large, blinded trials on adult patients have led to increasing use of these devices in pediatric patients. Although there are no prospective data to support device therapy in pediatric patients, several large, retrospective studies suggest that pediatric patients are likely to enjoy the same reduction in mortality as adult patients, with a slightly higher rate of complications from the device implant. Data on the use of these devices in pediatric patients for several different indications exist but are limited to retrospective reviews with small numbers and short follow-up. Large prospective trials are needed to assess the safety and efficacy of these devices in children and the influence of implant technique, patient growth, and programmed parameters on overall outcome.

Adolescent↗
PubMed2002

Ras processing as a therapeutic target in hematologic malignancies.

Knowledge of signal transduction pathways has uncovered therapeutic targets for cancer. Based on genetic and biochemical studies of leukemia cells, inhibiting hyperactive Ras represents a rational therapeutic strategy for many hematologic malignancies. Because posttranslational processing by farnesyltransferase is essential for transformation by oncogenic Ras, specific inhibitors of this enzyme are being evaluated as cancer therapeutics. The authors review recent laboratory insights on farnesyltransferase biology and on the development of inhibitors, summarize preclinical and clinical data in myeloid malignancies, and briefly discuss other strategies of interfering with hyperactive Ras.

Alkyl and Aryl Transferases↗