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

Parameswaran R, Yu M, Lyu MA, Lim M, Rosenblum MG, Groffen J, Heisterkamp N - Leukemia (2012)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Section of Molecular Carcinogenesis, Division of Hematology/Oncology and The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.

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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rGel/BLyS treatment down-regulates survival genes and inhibits NF-κB activation in ALL cells(A) Comparison of viability (left) and viable cell numbers (right) during long-term vincristine or rGel/BLyS treatment of US.7 cells. Fresh rGel/BLyS or vincristine was added every alternate day (n=2). (B) Expression of Bcl-xL, Mcl-1, Bcl-2, and Survivin in US7 cells, untreated or exposed to rGel/BLyS or rGel (100 nM) for 3 days (n=2). Isotype (black), untreated (blue), rGel (red) and rGel/BLyS (yellow). (C) Western blot for nuclear p65 expression in US.7 cells after 3 days incubation with different doses of rGel/BLyS or rGel, as indicated. Lamin, loading control.
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Figure 3: rGel/BLyS treatment down-regulates survival genes and inhibits NF-κB activation in ALL cells(A) Comparison of viability (left) and viable cell numbers (right) during long-term vincristine or rGel/BLyS treatment of US.7 cells. Fresh rGel/BLyS or vincristine was added every alternate day (n=2). (B) Expression of Bcl-xL, Mcl-1, Bcl-2, and Survivin in US7 cells, untreated or exposed to rGel/BLyS or rGel (100 nM) for 3 days (n=2). Isotype (black), untreated (blue), rGel (red) and rGel/BLyS (yellow). (C) Western blot for nuclear p65 expression in US.7 cells after 3 days incubation with different doses of rGel/BLyS or rGel, as indicated. Lamin, loading control.

Mentions: Vincristine is a commonly used toxic chemotherapeutic agent for the treatment of ALL. We therefore further compared the cytotoxic effect of rGel/BLyS to that of vincristine as monotreatment using US.7 cells. As shown in Figure 3A, 100 nM rGel/BLyS reduced viability of US7 cells to a similar extent as 2.5 nM vincristine, and suppressed proliferation of the cells in the presence of stroma (Figure 3A, right panel).


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

Parameswaran R, Yu M, Lyu MA, Lim M, Rosenblum MG, Groffen J, Heisterkamp N - Leukemia (2012)

rGel/BLyS treatment down-regulates survival genes and inhibits NF-κB activation in ALL cells(A) Comparison of viability (left) and viable cell numbers (right) during long-term vincristine or rGel/BLyS treatment of US.7 cells. Fresh rGel/BLyS or vincristine was added every alternate day (n=2). (B) Expression of Bcl-xL, Mcl-1, Bcl-2, and Survivin in US7 cells, untreated or exposed to rGel/BLyS or rGel (100 nM) for 3 days (n=2). Isotype (black), untreated (blue), rGel (red) and rGel/BLyS (yellow). (C) Western blot for nuclear p65 expression in US.7 cells after 3 days incubation with different doses of rGel/BLyS or rGel, as indicated. Lamin, loading control.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3376225&req=5

Figure 3: rGel/BLyS treatment down-regulates survival genes and inhibits NF-κB activation in ALL cells(A) Comparison of viability (left) and viable cell numbers (right) during long-term vincristine or rGel/BLyS treatment of US.7 cells. Fresh rGel/BLyS or vincristine was added every alternate day (n=2). (B) Expression of Bcl-xL, Mcl-1, Bcl-2, and Survivin in US7 cells, untreated or exposed to rGel/BLyS or rGel (100 nM) for 3 days (n=2). Isotype (black), untreated (blue), rGel (red) and rGel/BLyS (yellow). (C) Western blot for nuclear p65 expression in US.7 cells after 3 days incubation with different doses of rGel/BLyS or rGel, as indicated. Lamin, loading control.
Mentions: Vincristine is a commonly used toxic chemotherapeutic agent for the treatment of ALL. We therefore further compared the cytotoxic effect of rGel/BLyS to that of vincristine as monotreatment using US.7 cells. As shown in Figure 3A, 100 nM rGel/BLyS reduced viability of US7 cells to a similar extent as 2.5 nM vincristine, and suppressed proliferation of the cells in the presence of stroma (Figure 3A, right panel).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Section of Molecular Carcinogenesis, Division of Hematology/Oncology and The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.

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.

Show MeSH
Related in: MedlinePlus