Supplementary Figure S6 from Maturation Stage of T-cell Acute Lymphoblastic Leukemia Determines BCL-2 versus BCL-XL Dependence and Sensitivity to ABT-199

Chonghaile, Triona Ni; Roderick, Justine E.; Glenfield, Cian; Ryan, Jeremy; Sallan, Stephen E.; Silverman, Lewis B.; Loh, Mignon L.; Hunger, Stephen P.; Wood, Brent; DeAngelo, Daniel J.; Stone, Richard; Harris, Marian; Gutierrez, Alejandro; Kelliher, Michelle A.; Letai, Anthony

doi:10.1158/2159-8290.22531948.v1

Supplementary Figure S6 from Maturation Stage of T-cell Acute Lymphoblastic Leukemia Determines BCL-2 versus BCL-XL Dependence and Sensitivity to ABT-199

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posted on 2023-04-03, 21:22 authored by Triona Ni Chonghaile, Justine E. Roderick, Cian Glenfield, Jeremy Ryan, Stephen E. Sallan, Lewis B. Silverman, Mignon L. Loh, Stephen P. Hunger, Brent Wood, Daniel J. DeAngelo, Richard Stone, Marian Harris, Alejandro Gutierrez, Michelle A. Kelliher, Anthony Letai

<p>NSG mice were injected in the tail with either ETP-ALL (TALL-x-11) or typical T-ALL (TALL-x-2) 1X106 cells and following engraftment to 65% the mice were randomized to receive vehicle, ABT-199 or ABT-263 treatment for two-weeks. The spleen weights (A) and absolute human CD45+ counts (B) along with % human CD45+ cell in the blood (C) were measured for the ETP-ALL primagraft following treatment. The leg bones were harvested and representative images are shown for the different treatments (D). Similar experiments were performed for the typical T-ALL primagraft spleen weights (E), absolute human CD45+ count in the spleen (F) with % human CD45+ cells in the blood were measured (G). Similarly the legs bones were harvested and representative images are shown (H).</p>

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DOI - Is supplement to Maturation Stage of T-cell Acute Lymphoblastic Leukemia Determines BCL-2 versus BCL-XL Dependence and Sensitivity to ABT-199

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Acute lymphoblastic leukemia (ALL) is a hematopoietic malignancy derived from immature B-lymphoid and T-lymphoid cells (T-ALL). In T-ALL, there is an early T-cell progenitor (ETP) subgroup that has a very high risk for relapse. In this study, we used mitochondrial BH3 profiling to determine antiapoptotic protein dependencies in T-ALL. We found that T-ALL cell lines and primary patient samples are dependent upon BCL-XL, except when the cancer bears an ETP phenotype, in which case it is BCL-2 dependent. These distinctions directly relate to differential sensitivity to the BH3 mimetics ABT-263 and ABT-199, both in vitro and in vivo. We thus describe for the first time a change of antiapoptotic protein dependence that is related to the differentiation stage of the leukemic clone. Our findings demonstrate that BCL-2 is a clinically relevant target for therapeutic intervention with ABT-199 in ETP-ALL.Significance: ETP T-ALL is a treatment-resistant subtype of T-ALL for which novel targeted therapies are urgently needed. We have discovered, through BH3 profiling, that ETP-ALL is BCL-2 dependent and is very sensitive to in vitro and in vivo treatment with ABT-199, a drug well tolerated in clinical trials. Cancer Discov; 4(9); 1074–87. ©2014 AACR.This article is highlighted in the In This Issue feature, p. 973

Supplementary Figure S6 from Maturation Stage of T-cell Acute Lymphoblastic Leukemia Determines BCL-2 versus BCL-XL Dependence and Sensitivity to ABT-199

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