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BCL2-specific inhibitor ABT-199 synergizes strongly with cytarabine against the early immature LOUCY cell line but not more-differentiated T-ALL cell lines

Leukemia volume 28, pages 1145–1148 (2014)Cite this article

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T-cell acute lymphoblastic leukemia (T-ALL) arises from the malignant transformation of T-cell progenitors at various stages of development.1 Although significant strides have been made in the treatment of pediatric T-ALL with more than 80% of the patients now being cured of their disease,2 the early immature subtype of T-ALL has a dire prognosis with a 10-year overall survival of only 19%.3, 4 Early immature T-ALL is characterized by a gene expression signature related to early T-cell precursors and a distinct immunophenotype: CD1a−, CD8−, CD5weak with expression of stem-cell/myeloid markers.3, 4 In addition, this subtype of T-ALL harbors a distinct panel of mutations in genes that are commonly disrupted in acute myeloid leukemia.4, 5, 6 Although the genetic lesions characterizing early immature T-ALL have recently been described,6 the molecular basis underlying the inherent chemoresistance of this subtype of T-ALL remains largely unknown.

The high relapse rates of several lymphoid malignancies have been attributed to upregulation of anti-apoptotic BCL2 family members.7 BH3 mimetics, a class of small molecules that mimic BH3-only pro-apoptotic proteins, engage pro-survival BCL2 family proteins to promote cell death.8 Navitoclax (ABT-263) targets BCL-XL, BCL2 and BCLw; however, its use in the clinic has been limited because BCL-XL inhibition results in thrombocytopenia.9, 10, 11, 12 ABT-199, an investigational drug in clinical trials, is a potent BCL2 inhibitor that has minimal activity against BCL-XL and thus does not affect platelet survival.12 ABT-199 elicits striking pro-apoptotic effects as a single agent on non-Hodgkin’s lymphoma cell lines and chronic lymphocytic leukemia primary samples, both in vitro and in vivo.12 We therefore explored the hypothesis that anti-apoptotic BCL2 family proteins are required for the aberrant survival and chemotherapy resistance of T-ALL cells.

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Acknowledgements

This study was supported by 4R00CA134743 and ACS Grant IRG-72-001-36 to HF; and 1R01 CA176746 and P01 CA109901 to ATL. The authors thank J Etchin, A Kentsis and R Segal for reagents. IH acknowledges training support through NHLB1 T32 HL7501.

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Author notes

  1. N M Anderson and I Harrold: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology & Experimental Therapeutics, The Center for Cancer Research, Section of Hematology and Medical Oncology, Boston University School of Medicine, Boston, MA, USA

    N M Anderson, I Harrold, N Nagykary & H Feng

  2. Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, MA, USA

    M R Mansour & A T Look

  3. Department of Haematology, University College London Cancer Institute, University College London, London, UK

    M R Mansour

  4. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore

    T Sanda

  5. Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA

    M McKeown & J E Bradner

  6. Department of Computer Science, Metropolitan College, Boston University, Boston, MA, USA

    G Lan Zhang

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  1. N M Anderson
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Correspondence to A T Look or H Feng.

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Anderson, N., Harrold, I., Mansour, M. et al. BCL2-specific inhibitor ABT-199 synergizes strongly with cytarabine against the early immature LOUCY cell line but not more-differentiated T-ALL cell lines. Leukemia 28, 1145–1148 (2014). https://doi.org/10.1038/leu.2013.377

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