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Inhibition of BTK and PI3Kδ impairs the development of human JMML stem and progenitor cells
Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasia that lacks effective targeted chemotherapies. Clinically, JMML manifests as monocytic leukocytosis, splenomegaly with consequential thrombocytopenia. Most commonly, patients have gain-of-function (GOF) oncogenic mu...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9263321/ https://www.ncbi.nlm.nih.gov/pubmed/35443935 http://dx.doi.org/10.1016/j.ymthe.2022.04.009 |
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author | Ramdas, Baskar Yuen, Lisa Deng Palam, Lakshmi Reddy Patel, Roshini Pasupuleti, Santhosh Kumar Jideonwo, Victoria Zhang, Ji Maguire, Callista Wong, Eric Kanumuri, Rahul Zhang, Chujing Sandusky, George Chan, Rebecca J. Zhang, Chi Stieglitz, Elliot Haneline, Laura Kapur, Reuben |
author_facet | Ramdas, Baskar Yuen, Lisa Deng Palam, Lakshmi Reddy Patel, Roshini Pasupuleti, Santhosh Kumar Jideonwo, Victoria Zhang, Ji Maguire, Callista Wong, Eric Kanumuri, Rahul Zhang, Chujing Sandusky, George Chan, Rebecca J. Zhang, Chi Stieglitz, Elliot Haneline, Laura Kapur, Reuben |
author_sort | Ramdas, Baskar |
collection | PubMed |
description | Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasia that lacks effective targeted chemotherapies. Clinically, JMML manifests as monocytic leukocytosis, splenomegaly with consequential thrombocytopenia. Most commonly, patients have gain-of-function (GOF) oncogenic mutations in PTPN11 (SHP2), leading to Erk and Akt hyperactivation. Mechanism(s) involved in co-regulation of Erk and Akt in the context of GOF SHP2 are poorly understood. Here, we show that Bruton’s tyrosine kinase (BTK) is hyperphosphorylated in GOF Shp2-bearing cells and utilizes B cell adaptor for PI3K to cooperate with p110δ, the catalytic subunit of PI3K. Dual inhibition of BTK and p110δ reduces the activation of both Erk and Akt. In vivo, individual targeting of BTK or p110δ in a mouse model of human JMML equally reduces monocytosis and splenomegaly; however, the combined treatment results in a more robust inhibition and uniquely rescues anemia and thrombocytopenia. RNA-seq analysis of drug-treated mice showed a profound reduction in the expression of genes associated with leukemic cell migration and inflammation, leading to correction in the infiltration of leukemic cells in the lung, liver, and spleen. Remarkably, in a patient derived xenograft model of JMML, leukemia-initiating stem and progenitor cells were potently inhibited in response to the dual drug treatment. |
format | Online Article Text |
id | pubmed-9263321 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-92633212023-07-06 Inhibition of BTK and PI3Kδ impairs the development of human JMML stem and progenitor cells Ramdas, Baskar Yuen, Lisa Deng Palam, Lakshmi Reddy Patel, Roshini Pasupuleti, Santhosh Kumar Jideonwo, Victoria Zhang, Ji Maguire, Callista Wong, Eric Kanumuri, Rahul Zhang, Chujing Sandusky, George Chan, Rebecca J. Zhang, Chi Stieglitz, Elliot Haneline, Laura Kapur, Reuben Mol Ther Original Article Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasia that lacks effective targeted chemotherapies. Clinically, JMML manifests as monocytic leukocytosis, splenomegaly with consequential thrombocytopenia. Most commonly, patients have gain-of-function (GOF) oncogenic mutations in PTPN11 (SHP2), leading to Erk and Akt hyperactivation. Mechanism(s) involved in co-regulation of Erk and Akt in the context of GOF SHP2 are poorly understood. Here, we show that Bruton’s tyrosine kinase (BTK) is hyperphosphorylated in GOF Shp2-bearing cells and utilizes B cell adaptor for PI3K to cooperate with p110δ, the catalytic subunit of PI3K. Dual inhibition of BTK and p110δ reduces the activation of both Erk and Akt. In vivo, individual targeting of BTK or p110δ in a mouse model of human JMML equally reduces monocytosis and splenomegaly; however, the combined treatment results in a more robust inhibition and uniquely rescues anemia and thrombocytopenia. RNA-seq analysis of drug-treated mice showed a profound reduction in the expression of genes associated with leukemic cell migration and inflammation, leading to correction in the infiltration of leukemic cells in the lung, liver, and spleen. Remarkably, in a patient derived xenograft model of JMML, leukemia-initiating stem and progenitor cells were potently inhibited in response to the dual drug treatment. American Society of Gene & Cell Therapy 2022-07-06 2022-04-20 /pmc/articles/PMC9263321/ /pubmed/35443935 http://dx.doi.org/10.1016/j.ymthe.2022.04.009 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Article Ramdas, Baskar Yuen, Lisa Deng Palam, Lakshmi Reddy Patel, Roshini Pasupuleti, Santhosh Kumar Jideonwo, Victoria Zhang, Ji Maguire, Callista Wong, Eric Kanumuri, Rahul Zhang, Chujing Sandusky, George Chan, Rebecca J. Zhang, Chi Stieglitz, Elliot Haneline, Laura Kapur, Reuben Inhibition of BTK and PI3Kδ impairs the development of human JMML stem and progenitor cells |
title | Inhibition of BTK and PI3Kδ impairs the development of human JMML stem and progenitor cells |
title_full | Inhibition of BTK and PI3Kδ impairs the development of human JMML stem and progenitor cells |
title_fullStr | Inhibition of BTK and PI3Kδ impairs the development of human JMML stem and progenitor cells |
title_full_unstemmed | Inhibition of BTK and PI3Kδ impairs the development of human JMML stem and progenitor cells |
title_short | Inhibition of BTK and PI3Kδ impairs the development of human JMML stem and progenitor cells |
title_sort | inhibition of btk and pi3kδ impairs the development of human jmml stem and progenitor cells |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9263321/ https://www.ncbi.nlm.nih.gov/pubmed/35443935 http://dx.doi.org/10.1016/j.ymthe.2022.04.009 |
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