Trp53 loss during in vitro selection contributes to acquired Ara-C resistance in acute myeloid leukemia.

Experimental Hematology
B YinD A Largaespada

Abstract

Chemoresistance remains a major clinical obstacle to curative chemotherapy of acute myeloid leukemia (AML), but the molecular mechanisms underlying resistance to chemotherapeutic agents used in AML are largely unknown. We have attempted to investigate genetic mechanisms causing resistance to Ara-C [1-beta-D-arabinofuranosyl-cytosine (cytarabine)], one mainstay in AML chemotherapy for decades. Highly Ara-C-resistant murine BXH-2 strain AML cell lines were generated, and their molecular changes were compared to their sensitive parental lines. The causative changes were confirmed using a genetic approach. We derived nine highly Ara-C-resistant murine BXH-2 strain AML sublines via in vitro selection. p21Cip1 was dramatically downregulated and p53 protein accumulation induced by Ara-C treatment was impaired in one resistant line. In this line, repeated Ara-C exposure had selected for cells that harbor a genomic deletion affecting the splicing of Trp53 mRNA. This deletion produces an aberrant Trp53 mRNA, in which exon 4 is skipped, producing a protein lacking parts of both the transactivation and DNA-binding domains. Retroviral transduction of the sensitive parental cells with a dominant-negative Trp53 cDNA caused changes in the prot...Continue Reading

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Citations

Apr 3, 2009·Genes & Development·Johannes ZuberScott W Lowe
Oct 24, 2007·Molecular Pharmacology·Natalia KrynetskaiaEvgeny Krynetskiy
Aug 7, 2008·Blood·Andrew J SteeleR Gitendra Wickremasinghe
Oct 22, 2009·Pharmacogenomics·Jatinder K Lamba
Jun 2, 2007·Expert Opinion on Drug Metabolism & Toxicology·Donal P McLornanDaniel B Longley
Feb 4, 2011·Experimental Hematology·Timothy S PardeeScott W Lowe
Jan 27, 2015·The Journal of Clinical Investigation·Yogen SaunthararajahJaroslaw Maciejewski
Jun 11, 2016·Leukemia Research·Jiawei YinBin Yin
Jan 19, 2017·Current Opinion in Hematology·Sabine BlumMichael Lübbert
Aug 19, 2007·BioTechniques·Bin Yin, David A Largaespada
Jul 16, 2020·Inflammation and Regeneration·Maho MorimatsuMasaru Ishii

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