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Therapeutic Targeting of MERTK and BCL-2 in T-Cell and Early T-Precursor Acute Lymphoblastic Leukemia

SIMPLE SUMMARY: Children with T-cell leukemia (T-ALL) who experience relapse have a low chance of a cure with current therapy; so, new medicines are needed. MERTK and BCL-2 are proteins that may be therapeutic targets in children with T-ALL. In this research we tested whether treatments targeting ME...

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Autores principales: Summers, Ryan J., Jain, Juhi, Vasileiadi, Eleana, Smith, Brittany, Chimenti, Madison L., Yeung, Tsz Y., Kelvin, James, Wang, Xiaodong, Frye, Stephen V., Earp, H. Shelton, Tyner, Jeffrey W., Dreaden, Erik C., DeRyckere, Deborah, Graham, Douglas K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9776749/
https://www.ncbi.nlm.nih.gov/pubmed/36551626
http://dx.doi.org/10.3390/cancers14246142
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author Summers, Ryan J.
Jain, Juhi
Vasileiadi, Eleana
Smith, Brittany
Chimenti, Madison L.
Yeung, Tsz Y.
Kelvin, James
Wang, Xiaodong
Frye, Stephen V.
Earp, H. Shelton
Tyner, Jeffrey W.
Dreaden, Erik C.
DeRyckere, Deborah
Graham, Douglas K.
author_facet Summers, Ryan J.
Jain, Juhi
Vasileiadi, Eleana
Smith, Brittany
Chimenti, Madison L.
Yeung, Tsz Y.
Kelvin, James
Wang, Xiaodong
Frye, Stephen V.
Earp, H. Shelton
Tyner, Jeffrey W.
Dreaden, Erik C.
DeRyckere, Deborah
Graham, Douglas K.
author_sort Summers, Ryan J.
collection PubMed
description SIMPLE SUMMARY: Children with T-cell leukemia (T-ALL) who experience relapse have a low chance of a cure with current therapy; so, new medicines are needed. MERTK and BCL-2 are proteins that may be therapeutic targets in children with T-ALL. In this research we tested whether treatments targeting MERTK and BCL-2 are effective in experimental models of T-ALL. We found that MERTK and BCL-2 are present in some T-ALL cells and showed that a new drug called MRX-2843, which blocks MERTK function, can kill T-ALL cells. In mice with T-ALL, treatment with MRX-2843 reduced the presence of leukemia cells and prolonged survival. We also found that MRX-2843 provided more effective T-ALL cell killing when it was combined with another drug called venetoclax, which blocks BCL-2 function. These studies provide good evidence that MRX-2843 could be effective for treatment of T-ALL, especially when combined with venetoclax. ABSTRACT: T-cell acute lymphoblastic leukemia (T-ALL) accounts for 15% of childhood ALL. The early T-precursor (ETP-ALL) subset is characterized by an immature T-cell phenotype, chemoresistance, and high rates of induction failure. MERTK receptor tyrosine kinase is ectopically expressed in half of T-ALLs, particularly those with an immature T-cell phenotype, suggesting a role in ETP-ALL. The anti-apoptotic protein B-cell lymphoma-2 (BCL-2) is essential for ETP-ALL cell survival. Here, we show that MERTK and BCL-2 mRNA and protein are preferentially expressed in ETP-ALL patient samples. The dual MERTK/FLT3 inhibitor MRX-2843 decreased MERTK activation and downstream signaling, inhibited cell expansion, and induced cell death in ETP-ALL cell lines. Further, 54% (21/39) of primary T-ALL patient samples were sensitive to MERTK inhibition. Treatment with MRX-2843 significantly reduced leukemia burden and prolonged survival in cell-line-derived T-ALL and ETP-ALL xenograft models. In a patient-derived ETP-ALL xenograft model, treatment with MRX-2843 markedly reduced peripheral blood leukemia and spleen weight compared to vehicle-treated mice and prolonged survival. MRX-2843 also synergized with venetoclax to provide enhanced anti-leukemia activity in ETP-ALL cell cultures, with a dose ratio of 1:20 MRX-2843:venetoclax providing optimal synergy. These data demonstrate the therapeutic potential of MRX-2843 in patients with T-ALL and provide rationale for clinical development. MRX-2843 monotherapy is currently being tested in patients with relapsed leukemia (NCT04872478). Further, our data indicate that combined MERTK and BCL-2 inhibition may be particularly effective for treatment of ETP-ALL.
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spelling pubmed-97767492022-12-23 Therapeutic Targeting of MERTK and BCL-2 in T-Cell and Early T-Precursor Acute Lymphoblastic Leukemia Summers, Ryan J. Jain, Juhi Vasileiadi, Eleana Smith, Brittany Chimenti, Madison L. Yeung, Tsz Y. Kelvin, James Wang, Xiaodong Frye, Stephen V. Earp, H. Shelton Tyner, Jeffrey W. Dreaden, Erik C. DeRyckere, Deborah Graham, Douglas K. Cancers (Basel) Article SIMPLE SUMMARY: Children with T-cell leukemia (T-ALL) who experience relapse have a low chance of a cure with current therapy; so, new medicines are needed. MERTK and BCL-2 are proteins that may be therapeutic targets in children with T-ALL. In this research we tested whether treatments targeting MERTK and BCL-2 are effective in experimental models of T-ALL. We found that MERTK and BCL-2 are present in some T-ALL cells and showed that a new drug called MRX-2843, which blocks MERTK function, can kill T-ALL cells. In mice with T-ALL, treatment with MRX-2843 reduced the presence of leukemia cells and prolonged survival. We also found that MRX-2843 provided more effective T-ALL cell killing when it was combined with another drug called venetoclax, which blocks BCL-2 function. These studies provide good evidence that MRX-2843 could be effective for treatment of T-ALL, especially when combined with venetoclax. ABSTRACT: T-cell acute lymphoblastic leukemia (T-ALL) accounts for 15% of childhood ALL. The early T-precursor (ETP-ALL) subset is characterized by an immature T-cell phenotype, chemoresistance, and high rates of induction failure. MERTK receptor tyrosine kinase is ectopically expressed in half of T-ALLs, particularly those with an immature T-cell phenotype, suggesting a role in ETP-ALL. The anti-apoptotic protein B-cell lymphoma-2 (BCL-2) is essential for ETP-ALL cell survival. Here, we show that MERTK and BCL-2 mRNA and protein are preferentially expressed in ETP-ALL patient samples. The dual MERTK/FLT3 inhibitor MRX-2843 decreased MERTK activation and downstream signaling, inhibited cell expansion, and induced cell death in ETP-ALL cell lines. Further, 54% (21/39) of primary T-ALL patient samples were sensitive to MERTK inhibition. Treatment with MRX-2843 significantly reduced leukemia burden and prolonged survival in cell-line-derived T-ALL and ETP-ALL xenograft models. In a patient-derived ETP-ALL xenograft model, treatment with MRX-2843 markedly reduced peripheral blood leukemia and spleen weight compared to vehicle-treated mice and prolonged survival. MRX-2843 also synergized with venetoclax to provide enhanced anti-leukemia activity in ETP-ALL cell cultures, with a dose ratio of 1:20 MRX-2843:venetoclax providing optimal synergy. These data demonstrate the therapeutic potential of MRX-2843 in patients with T-ALL and provide rationale for clinical development. MRX-2843 monotherapy is currently being tested in patients with relapsed leukemia (NCT04872478). Further, our data indicate that combined MERTK and BCL-2 inhibition may be particularly effective for treatment of ETP-ALL. MDPI 2022-12-13 /pmc/articles/PMC9776749/ /pubmed/36551626 http://dx.doi.org/10.3390/cancers14246142 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Summers, Ryan J.
Jain, Juhi
Vasileiadi, Eleana
Smith, Brittany
Chimenti, Madison L.
Yeung, Tsz Y.
Kelvin, James
Wang, Xiaodong
Frye, Stephen V.
Earp, H. Shelton
Tyner, Jeffrey W.
Dreaden, Erik C.
DeRyckere, Deborah
Graham, Douglas K.
Therapeutic Targeting of MERTK and BCL-2 in T-Cell and Early T-Precursor Acute Lymphoblastic Leukemia
title Therapeutic Targeting of MERTK and BCL-2 in T-Cell and Early T-Precursor Acute Lymphoblastic Leukemia
title_full Therapeutic Targeting of MERTK and BCL-2 in T-Cell and Early T-Precursor Acute Lymphoblastic Leukemia
title_fullStr Therapeutic Targeting of MERTK and BCL-2 in T-Cell and Early T-Precursor Acute Lymphoblastic Leukemia
title_full_unstemmed Therapeutic Targeting of MERTK and BCL-2 in T-Cell and Early T-Precursor Acute Lymphoblastic Leukemia
title_short Therapeutic Targeting of MERTK and BCL-2 in T-Cell and Early T-Precursor Acute Lymphoblastic Leukemia
title_sort therapeutic targeting of mertk and bcl-2 in t-cell and early t-precursor acute lymphoblastic leukemia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9776749/
https://www.ncbi.nlm.nih.gov/pubmed/36551626
http://dx.doi.org/10.3390/cancers14246142
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