Loss in MCL-1 function sensitizes non-Hodgkin's lymphoma cell lines to the BCL-2-selective inhibitor venetoclax (ABT-199)

Blood Cancer J. 2015 Nov 13;5(11):e368. doi: 10.1038/bcj.2015.88.


As a population, non-Hodgkin's lymphoma (NHL) cell lines positive for the t(14;18) translocation and/or possessing elevated BCL2 copy number (CN; BCL2(High)) are exquisitely sensitive to navitoclax or the B-cell lymphoma protein-2 (BCL-2)-selective inhibitor venetoclax. Despite this, some BCL2(High) cell lines remain resistant to either agent. Here we show that the MCL-1-specific inhibitor A-1210477 sensitizes these cell lines to navitoclax. Chemical segregation of this synergy with the BCL-2-selective inhibitor venetoclax or BCL-XL-selective inhibitor A-1155463 indicated that MCL-1 and BCL-2 are the two key anti-apoptotic targets for sensitization. Similarly, the CDK inhibitor flavopiridol downregulated MCL-1 expression and synergized with venetoclax in BCL2(High) NHL cell lines to a similar extent as A-1210477. A-1210477 also synergized with navitoclax in the majority of BCL2(Low) NHL cell lines. However, chemical segregation with venetoclax or A-1155463 revealed that synergy was driven by BCL-XL inhibition in this population. Collectively these data emphasize that BCL2 status is predictive of venetoclax potency in NHL not only as a single agent, but also in the adjuvant setting with anti-tumorigenic agents that inhibit MCL-1 function. These studies also potentially identify a patient population (BCL2(Low)) that could benefit from BCL-XL (navitoclax)-driven combination therapy.

MeSH terms

  • Aniline Compounds / pharmacology
  • Antineoplastic Agents / pharmacology
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
  • Cell Line, Tumor
  • Drug Synergism
  • Humans
  • Indoles / pharmacology
  • Lymphoma, Non-Hodgkin / drug therapy*
  • Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Sulfonamides / pharmacology*
  • bcl-X Protein / antagonists & inhibitors*


  • A-1210477
  • Aniline Compounds
  • Antineoplastic Agents
  • Bridged Bicyclo Compounds, Heterocyclic
  • Indoles
  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Proto-Oncogene Proteins c-bcl-2
  • Sulfonamides
  • bcl-X Protein
  • venetoclax
  • navitoclax