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The spleen as a sanctuary site for residual leukemic cells following ABT-199 monotherapy in ETP-ALL

(2021) BLOOD ADVANCES. 5(7). p.1963-1976
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Abstract
B-cell lymphoma 2 (BCL-2) has recently emerged as a therapeutic target for early T-cell progenitor acute lymphoblastic leukemia (ETP-ALL), a high-risk subtype of human T-cell ALL. The major clinical challenge with targeted therapeutics, such as the BCL-2 inhibitor ABT-199, is the development of acquired resistance. We assessed the in vivo response of luciferase-positive LOUCY cells to ABT-199 monotherapy and observed specific residual disease in the splenic microenvironment. Of note, these results were confirmed by using a primary ETP-ALL patient-derived xenograft. Splenomegaly has previously been associated with poor prognosis in diverse types of leukemia. However, the exact mechanism by which the splenic microenvironment alters responses to specific targeted therapies remains largely unexplored. We show that residual LOUCY cells isolated from the spleen microenvironment displayed reduced BCL-2 dependence, which was accompanied by decreased BCL-2 expression levels. Notably, this phenotype of reduced BCL-2 dependence could be recapitulated by using human splenic fibroblast coculture experiments and was confirmed in an in vitro chronic ABT-199 resistance model of LOUCY. Finally, single-cell RNA-sequencing was used to show that ABT-199 triggers transcriptional changes in T-cell differentiation genes in leukemic cells obtained from the spleen microenvironment. Of note, increased expression of CD1a and 5CD3 was also observed in ABT199-resistant LOUCY Bones, further reinforcing the idea that a more differentiated leukemic population might display decreased sensitivity toward BCL-2 inhibition. Overall, our data reveal the spleen as a site of residual disease for ABT-199 treatment in ETP-ALL and provide evidence for plasticity in T-cell differentiation as a mechanism of therapy resistance.
Keywords
ACUTE LYMPHOBLASTIC-LEUKEMIA, BONE-MARROW MICROENVIRONMENT, PROGNOSTIC-FACTORS, MYELOID-LEUKEMIA, RESISTANCE, BCL-2, INHIBITION, SPLENECTOMY, VENETOCLAX, DEPENDENCE

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MLA
Di Grande, Alessandra, et al. “The Spleen as a Sanctuary Site for Residual Leukemic Cells Following ABT-199 Monotherapy in ETP-ALL.” BLOOD ADVANCES, vol. 5, no. 7, 2021, pp. 1963–76, doi:10.1182/bloodadvances.2021004177.
APA
Di Grande, A., Peirs, S., Donovan, P. D., Van Trimpont, M., Morscio, J., Lintermans, B., … Ní Chonghaile, T. (2021). The spleen as a sanctuary site for residual leukemic cells following ABT-199 monotherapy in ETP-ALL. BLOOD ADVANCES, 5(7), 1963–1976. https://doi.org/10.1182/bloodadvances.2021004177
Chicago author-date
Di Grande, Alessandra, Sofie Peirs, Paul D. Donovan, Maaike Van Trimpont, Julie Morscio, Béatrice Lintermans, Lindy Reunes, et al. 2021. “The Spleen as a Sanctuary Site for Residual Leukemic Cells Following ABT-199 Monotherapy in ETP-ALL.” BLOOD ADVANCES 5 (7): 1963–76. https://doi.org/10.1182/bloodadvances.2021004177.
Chicago author-date (all authors)
Di Grande, Alessandra, Sofie Peirs, Paul D. Donovan, Maaike Van Trimpont, Julie Morscio, Béatrice Lintermans, Lindy Reunes, Niels Vandamme, Steven Goossens, Hien Anh Nguyen, Arnon Lavie, Richard B. Lock, Jochen H. M. Prehn, Pieter Van Vlierberghe, and Triona Ní Chonghaile. 2021. “The Spleen as a Sanctuary Site for Residual Leukemic Cells Following ABT-199 Monotherapy in ETP-ALL.” BLOOD ADVANCES 5 (7): 1963–1976. doi:10.1182/bloodadvances.2021004177.
Vancouver
1.
Di Grande A, Peirs S, Donovan PD, Van Trimpont M, Morscio J, Lintermans B, et al. The spleen as a sanctuary site for residual leukemic cells following ABT-199 monotherapy in ETP-ALL. BLOOD ADVANCES. 2021;5(7):1963–76.
IEEE
[1]
A. Di Grande et al., “The spleen as a sanctuary site for residual leukemic cells following ABT-199 monotherapy in ETP-ALL,” BLOOD ADVANCES, vol. 5, no. 7, pp. 1963–1976, 2021.
@article{8704149,
  abstract     = {{B-cell lymphoma 2 (BCL-2) has recently emerged as a therapeutic target for early T-cell progenitor acute lymphoblastic leukemia (ETP-ALL), a high-risk subtype of human T-cell ALL. The major clinical challenge with targeted therapeutics, such as the BCL-2 inhibitor ABT-199, is the development of acquired resistance. We assessed the in vivo response of luciferase-positive LOUCY cells to ABT-199 monotherapy and observed specific residual disease in the splenic microenvironment. Of note, these results were confirmed by using a primary ETP-ALL patient-derived xenograft. Splenomegaly has previously been associated with poor prognosis in diverse types of leukemia. However, the exact mechanism by which the splenic microenvironment alters responses to specific targeted therapies remains largely unexplored. We show that residual LOUCY cells isolated from the spleen microenvironment displayed reduced BCL-2 dependence, which was accompanied by decreased BCL-2 expression levels. Notably, this phenotype of reduced BCL-2 dependence could be recapitulated by using human splenic fibroblast coculture experiments and was confirmed in an in vitro chronic ABT-199 resistance model of LOUCY. Finally, single-cell RNA-sequencing was used to show that ABT-199 triggers transcriptional changes in T-cell differentiation genes in leukemic cells obtained from the spleen microenvironment. Of note, increased expression of CD1a and 5CD3 was also observed in ABT199-resistant LOUCY Bones, further reinforcing the idea that a more differentiated leukemic population might display decreased sensitivity toward BCL-2 inhibition. Overall, our data reveal the spleen as a site of residual disease for ABT-199 treatment in ETP-ALL and provide evidence for plasticity in T-cell differentiation as a mechanism of therapy resistance.}},
  author       = {{Di Grande, Alessandra and Peirs, Sofie and Donovan, Paul D. and Van Trimpont, Maaike and Morscio, Julie and Lintermans, Béatrice and Reunes, Lindy and Vandamme, Niels and Goossens, Steven and Nguyen, Hien Anh and Lavie, Arnon and Lock, Richard B. and Prehn, Jochen H. M. and Van Vlierberghe, Pieter and Ní Chonghaile, Triona}},
  issn         = {{2473-9529}},
  journal      = {{BLOOD ADVANCES}},
  keywords     = {{ACUTE LYMPHOBLASTIC-LEUKEMIA,BONE-MARROW MICROENVIRONMENT,PROGNOSTIC-FACTORS,MYELOID-LEUKEMIA,RESISTANCE,BCL-2,INHIBITION,SPLENECTOMY,VENETOCLAX,DEPENDENCE}},
  language     = {{eng}},
  number       = {{7}},
  pages        = {{1963--1976}},
  title        = {{The spleen as a sanctuary site for residual leukemic cells following ABT-199 monotherapy in ETP-ALL}},
  url          = {{http://dx.doi.org/10.1182/bloodadvances.2021004177}},
  volume       = {{5}},
  year         = {{2021}},
}

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