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Multiple distinct molecular mechanisms influence sensitivity and resistance to MDM2 inhibitors in adult acute myelogenous leukemia.

Publication ,  Journal Article
Long, J; Parkin, B; Ouillette, P; Bixby, D; Shedden, K; Erba, H; Wang, S; Malek, SN
Published in: Blood
July 8, 2010

The survival of most patients with acute myelogenous leukemia (AML) remains poor, and novel therapeutic approaches are needed to improve outcomes. Given that the fraction of AML with mutated p53 is small ( approximately 10%), it appears rational to study MDM2 inhibitors as therapy for AML. Here, we report results of a detailed characterization of sensitivity and resistance to treatment ex vivo with the MDM2 inhibitor MI219 in AML blasts from 109 patients. In line with previous observations, all AML cases with mutated p53 were resistant to MI219. Importantly, approximately 30% of AML cases with unmutated p53 also demonstrated primary resistance to MI219. Analysis of potential mechanisms associated with MI219 resistance in AML blasts with wild-type p53 uncovered distinct molecular defects, including low or absent p53 protein induction after MDM2 inhibitor treatment or external irradiation. Furthermore, a separate subset of resistant blasts displayed robust p53 protein induction after MI219 treatment, indicative of defective p53 protein function or defects in the apoptotic p53 network. Finally, analysis of very sensitive AML cases uncovered a strong and significant association with mutated Flt3 status (Flt3-ITD), which for the first time identified a clinically high-risk group of AML that may particularly benefit from MDM2 inhibitor treatment.

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Published In

Blood

DOI

EISSN

1528-0020

Publication Date

July 8, 2010

Volume

116

Issue

1

Start / End Page

71 / 80

Location

United States

Related Subject Headings

  • fms-Like Tyrosine Kinase 3
  • Young Adult
  • Tumor Suppressor Protein p53
  • Tumor Cells, Cultured
  • Spiro Compounds
  • Reverse Transcriptase Polymerase Chain Reaction
  • Proto-Oncogene Proteins c-mdm2
  • Proto-Oncogene Proteins
  • Piperazines
  • Nuclear Proteins
 

Citation

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Long, J., Parkin, B., Ouillette, P., Bixby, D., Shedden, K., Erba, H., … Malek, S. N. (2010). Multiple distinct molecular mechanisms influence sensitivity and resistance to MDM2 inhibitors in adult acute myelogenous leukemia. Blood, 116(1), 71–80. https://doi.org/10.1182/blood-2010-01-261628
Long, Jianting, Brian Parkin, Peter Ouillette, Dale Bixby, Kerby Shedden, Harry Erba, Shaomeng Wang, and Sami N. Malek. “Multiple distinct molecular mechanisms influence sensitivity and resistance to MDM2 inhibitors in adult acute myelogenous leukemia.Blood 116, no. 1 (July 8, 2010): 71–80. https://doi.org/10.1182/blood-2010-01-261628.
Long J, Parkin B, Ouillette P, Bixby D, Shedden K, Erba H, et al. Multiple distinct molecular mechanisms influence sensitivity and resistance to MDM2 inhibitors in adult acute myelogenous leukemia. Blood. 2010 Jul 8;116(1):71–80.
Long, Jianting, et al. “Multiple distinct molecular mechanisms influence sensitivity and resistance to MDM2 inhibitors in adult acute myelogenous leukemia.Blood, vol. 116, no. 1, July 2010, pp. 71–80. Pubmed, doi:10.1182/blood-2010-01-261628.
Long J, Parkin B, Ouillette P, Bixby D, Shedden K, Erba H, Wang S, Malek SN. Multiple distinct molecular mechanisms influence sensitivity and resistance to MDM2 inhibitors in adult acute myelogenous leukemia. Blood. 2010 Jul 8;116(1):71–80.

Published In

Blood

DOI

EISSN

1528-0020

Publication Date

July 8, 2010

Volume

116

Issue

1

Start / End Page

71 / 80

Location

United States

Related Subject Headings

  • fms-Like Tyrosine Kinase 3
  • Young Adult
  • Tumor Suppressor Protein p53
  • Tumor Cells, Cultured
  • Spiro Compounds
  • Reverse Transcriptase Polymerase Chain Reaction
  • Proto-Oncogene Proteins c-mdm2
  • Proto-Oncogene Proteins
  • Piperazines
  • Nuclear Proteins