Treatment of Acute Lymphoblastic Leukemia With an rGel/BLyS Fusion Toxin

Leukemia. 2012 Aug;26(8):1786-96. doi: 10.1038/leu.2012.54. Epub 2012 Feb 29.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / therapeutic use*
  • Apoptosis / drug effects
  • B-Cell Activating Factor / administration & dosage
  • B-Cell Activating Factor / genetics
  • B-Cell Activating Factor / metabolism
  • B-Cell Activating Factor / therapeutic use*
  • Bone Marrow / pathology
  • Cell Line, Tumor
  • Drug Synergism
  • Gene Expression Regulation, Leukemic / drug effects
  • Heterocyclic Compounds / pharmacology
  • Humans
  • Mice
  • Mice, Nude
  • Mice, SCID
  • NF-kappa B / antagonists & inhibitors
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Recombinant Fusion Proteins / administration & dosage
  • Recombinant Fusion Proteins / metabolism
  • Recombinant Fusion Proteins / therapeutic use*
  • Ribosome Inactivating Proteins, Type 1 / administration & dosage
  • Ribosome Inactivating Proteins, Type 1 / genetics
  • Ribosome Inactivating Proteins, Type 1 / metabolism
  • Ribosome Inactivating Proteins, Type 1 / therapeutic use*
  • Toxins, Biological / administration & dosage
  • Toxins, Biological / metabolism
  • Toxins, Biological / therapeutic use
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • B-Cell Activating Factor
  • Heterocyclic Compounds
  • NF-kappa B
  • Recombinant Fusion Proteins
  • Ribosome Inactivating Proteins, Type 1
  • TNFSF13B protein, human
  • Toxins, Biological
  • rGel-BLyS fusion toxin
  • GEL protein, Gelonium multiflorum
  • plerixafor octahydrochloride