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Articles by M. J Keating
Total Records ( 3 ) for M. J Keating
  D. A Thomas , S O'Brien , J. L Jorgensen , J Cortes , S Faderl , G Garcia Manero , S Verstovsek , C Koller , S Pierce , Y Huh , W Wierda , M. J Keating and H. M. Kantarjian
 

Immunophenotypic classification of acute lymphoblastic leukemia (ALL) has well-recognized prognostic implications. The significance of CD20 expression has been evaluated in childhood precursor B-lineage ALL with conflicting results. We retrospectively analyzed the influence of CD20 expression on outcome in 253 adults with de novo precursor B-lineage ALL treated with either conventional (VAD/CVAD) or intensive (hyper-CVAD) frontline chemotherapy regimens in the pre-rituximab era. Overall, CD20 positivity of at least 20% was associated with lower 3-year rates of complete remission duration (CRD; 20% vs 55%, P < .001) and overall survival (OS; 27% vs 40%, p = .03). In the CD20 negative subset, the 3-year rates for CRD (58% vs 42%, p = .04) and OS (60% vs 28%, P < .001) were superior for hyper-CVAD compared with VAD/CVAD; rates were particularly favorable for the CD20 negative younger age group (68% and 85%, respectively). In contrast, 3-year CRD and OS rates were uniformly poor for the CD20-positive group regardless of therapy (27% or less). Multivariate analysis for event-free survival identified older age, leukocyte count higher than 30 x 109/L, presence of Philadelphia chromosome, high systemic risk classification, and CD20 positivity as independent predictors of worse outcome. In conclusion, CD20 expression in de novo adult precursor B-lineage ALL appears to be associated with a poor prognosis. Incorporation of monoclonal antibodies directed against CD20 into frontline chemotherapy regimens warrants investigation.

  S. E Wojcik , S Rossi , M Shimizu , M. S Nicoloso , A Cimmino , H Alder , V Herlea , L. Z Rassenti , K. R Rai , T. J Kipps , M. J Keating , C. M Croce and G. A. Calin
 

Cancer is a genetic disease in which the interplay between alterations in protein-coding genes and non-coding RNAs (ncRNAs) plays a fundamental role. In recent years, the full coding component of the human genome was sequenced in various cancers, whereas such attempts related to ncRNAs are still fragmentary. We screened genomic DNAs for sequence variations in 148 microRNAs (miRNAs) and ultraconserved regions (UCRs) loci in patients with chronic lymphocytic leukemia (CLL) or colorectal cancer (CRC) by Sanger technique and further tried to elucidate the functional consequences of some of these variations. We found sequence variations in miRNAs in both sporadic and familial CLL cases, mutations of UCRs in CLLs and CRCs and, in certain instances, detected functional effects of these variations. Furthermore, by integrating our data with previously published data on miRNA sequence variations, we have created a catalog of DNA sequence variations in miRNAs/ultraconserved genes in human cancers. These findings argue that ncRNAs are targeted by both germ line and somatic mutations as well as by single-nucleotide polymorphisms with functional significance for human tumorigenesis. Sequence variations in ncRNA loci are frequent and some have functional and biological significance. Such information can be exploited to further investigate on a genome-wide scale the frequency of genetic variations in ncRNAs and their functional meaning, as well as for the development of new diagnostic and prognostic markers for leukemias and carcinomas.

  C. Y Tsai , A. S Ray , D. B Tumas , M. J Keating , H Reiser and W. Plunkett
 

Purpose: GS-9219 is a cell-permeable prodrug of the acyclic nucleotide analogue 9-(2-phosphonylmethoxyethyl)guanine (PMEG); the incorporation of the active metabolite PMEG diphosphate (PMEGpp) into DNA results in DNA chain termination due to the lack of a 3'-hydroxyl moiety. We hypothesized that the incorporation of PMEGpp into DNA during repair resynthesis would result in the inhibition of DNA repair and the accumulation of DNA breaks in chronic lymphocytic leukemia (CLL) cells that would activate signaling pathways to cell death.

Experimental Design: To test this hypothesis, CLL cells were irradiated with UV light to stimulate nucleotide excision repair pathways, enabling the incorporation of PMEGpp into DNA. The combination effects of GS-9219 and DNA-damaging agents and the signaling mechanisms activated in response to DNA repair inhibition by GS-9219, as well as changes in CLL cell viability, were investigated.

Results: PMEGpp was incorporated into DNA in CLL cells when nucleotide excision repair was activated by UV. Following PMEGpp incorporation, DNA repair was inhibited, which led to the accumulation of DNA strand breaks. The presence of DNA strand breaks activated the phosphatidylinositol 3-kinase–like protein kinase family members ataxia-telangiectasia mutated and DNA-dependent protein kinase. P53 was phosphorylated and stabilized in response to the inhibition of DNA repair. P53 targeted proteins, Puma and Bax, were up-regulated and activated. The combination of GS-9219 and DNA-damaging agents resulted in more cell death than the sum of the single agents alone.

Conclusion: GS-9219 inhibits DNA repair in CLL cells, an action that stimulates signaling pathways for apoptosis induction.

 
 
 
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