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Acute Leukemias

Treatment of acute lymphoblastic leukemia with an rGel/BLyS fusion toxin

Leukemia volume 26, pages 1786–1796 (2012)Cite this article

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Abstract

Acute lymphoblastic leukemia (ALL) is the most common malignancy affecting children and a major cause of mortality from hematopoietic malignancies in adults. A substantial number of patients become drug resistant during chemotherapy, necessitating the development of alternative modes of treatment. rGel (recombinant Gelonin)/BlyS (B-lymphocyte stimulator) is a toxin-cytokine fusion protein used for selective killing of malignant B-cells expressing receptors for B-cell-activating factor (BAFF/BLyS) by receptor-targeted delivery of the toxin, Gelonin. Here, we demonstrate that rGel/BLyS binds to ALL cells expressing BAFF receptor (BAFF-R) and upon internalization, it induces apoptosis of these cells and causes downregulation of survival genes even in the presence of stromal protection. Using an immunodeficient transplant model for human ALL, we show that rGel/BLyS prolongs survival of both Philadelphia chromosome-positive and negative ALL-bearing mice. Furthermore, we used AMD3100, a CXCR4 antagonist, to mobilize the leukemic cells protected in the bone marrow (BM) microenvironment and the combination with rGel/BLyS resulted in a significant reduction of the tumor load in the BM and complete eradication of ALL cells from the circulation. Thus, a combination treatment with the B-cell-specific fusion toxin rGel/BLyS and the mobilizing agent AMD3100 could be an effective alternative approach to chemotherapy for the treatment of primary and relapsed ALL.

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Acknowledgements

We thank Donna Foster for excellent care of the mice. This work was supported by PHS grant CA090321 (to NH), by the William Lawrence and Blanche Hughes Foundation (to NH, JG), and a Translational Research Award (LLS 6234-07) from the Leukemia and Lymphoma Society (to MGR) and in part by the Clayton Foundation for Research (MGR). M-AL and MGR were supported by the Clayton Foundation.

Author contributions

RP designed and performed experiments, analyzed data and wrote the manuscript; MY and ML performed experiments and analyzed data; M-AL, MGR and JG contributed essential reagents and provided input in the design of experiments; NH designed experiments, analyzed data and wrote the manuscript.

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Authors and Affiliations

  1. Division of Hematology/Oncology and The Saban Research Institute, Section of Molecular Carcinogenesis, Children's Hospital Los Angeles, Los Angeles, CA, USA

    R Parameswaran, M Yu, M Lim, J Groffen & N Heisterkamp

  2. Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, TX, USA

    M-A Lyu & M G Rosenblum

  3. Leukemia Research Program, Children's Hospital Los Angeles, Los Angeles, CA, USA

    J Groffen & N Heisterkamp

  4. Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Southern California, CA, USA

    J Groffen & N Heisterkamp

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  1. R Parameswaran
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  2. M Yu
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  3. M-A Lyu
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Correspondence to N Heisterkamp.

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Parameswaran, R., Yu, M., Lyu, MA. et al. Treatment of acute lymphoblastic leukemia with an rGel/BLyS fusion toxin. Leukemia 26, 1786–1796 (2012). https://doi.org/10.1038/leu.2012.54

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