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

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

Torossian A1,2,3, Broin N1,2,3, Frentzel J1,2,3, Daugrois C1,2,3,4, Gandarillas S5, Saati TA6, Lamant L1,2,3,4,7,8, Brousset P1,2,3,4,7,8, Giuriato S9,2,3,8,10, Espinos E9,2,3,4,8.

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Inserm, UMR1037 CRCT, F-31000 Toulouse, France.
Université Toulouse III-Paul Sabatier, UMR1037 CRCT, F-31000 Toulouse, France.
CNRS, ERL5294 UMR1037 CRCT, F-31000, Toulouse, France.
Laboratoire d'Excellence Toulouse-Cancer-TOUCAN, F-31024 Toulouse, France.
Inserm/UPS, US006/CREFRE, F-31000 Toulouse, France.
Inserm/UPS, US006/CREFRE, Service d'Histopathologie, F-31000 Toulouse, France.
Département de Pathologie, IUCT, F-31000 Toulouse, France.
European Research Initiative on ALK-related Malignancies (ERIA), Cambridge, UK.
Inserm, UMR1037 CRCT, F-31000 Toulouse, France
Transautophagy: European network for multidisciplinary research and translation of autophagy knowledge, COST Action CA15138, Brussel, Belgium.


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.

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