Blockade of crizotinib-induced BCL2 elevation in ALK-positive anaplastic large cell lymphoma triggers autophagy associated with cell death

Haematologica. 2019 Jul;104(7):1428-1439. doi: 10.3324/haematol.2017.181966. Epub 2019 Jan 24.


Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphomas are tumors that carry translocations involving the ALK gene at the 2p23 locus, leading to the expression of ALK tyrosine kinase fusion oncoproteins. Amongst hematologic malignancies, these lymphomas are particular in that they express very low levels of B-cell lymphoma 2 (BCL2), a recognized inhibitor of apoptosis and autophagy, two processes that share complex interconnections. We have previously shown that treatment of ALK-positive anaplastic large cell lymphoma cells with the ALK tyrosine kinase inhibitor crizotinib induces autophagy as a pro-survival response. Here, we observed that crizotinib-mediated inactivation of ALK caused an increase in BCL2 levels that restrained the cytotoxic effects of the drug. BCL2 downregulation in combination with crizotinib treatment potentiated loss of cell viability through both an increase in autophagic flux and cell death, including apoptosis. More importantly, our data revealed that the blockade of autophagic flux completely reversed impaired cell viability, which demonstrates that excessive autophagy is associated with cell death. We propose that the downregulation of BCL2 protein, which plays a central role in the autophagic and apoptotic machinery, combined with crizotinib treatment may represent a promising therapeutic alternative to current ALK-positive anaplastic large cell lymphoma treatments.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaplastic Lymphoma Kinase / genetics
  • Anaplastic Lymphoma Kinase / metabolism*
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Autophagy*
  • Cell Death
  • Cell Proliferation / drug effects
  • Crizotinib / pharmacology*
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Lymphoma, Large-Cell, Anaplastic / drug therapy
  • Lymphoma, Large-Cell, Anaplastic / metabolism
  • Lymphoma, Large-Cell, Anaplastic / pathology*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Prognosis
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • BCL2 protein, human
  • Proto-Oncogene Proteins c-bcl-2
  • Crizotinib
  • ALK protein, human
  • Anaplastic Lymphoma Kinase