Bayesian multi-source regression and monocyte-associated gene expression predict BCL-2 inhibitor resistance in acute myeloid leukemia

Abstract The FDA recently approved eight targeted therapies for acute myeloid leukemia (AML), including the BCL-2 inhibitor venetoclax. Maximizing efficacy of these treatments requires refining patient selection. To this end, we analyzed two recent AML studies profiling the gene expression and ex vi...

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Autores principales:	Brian S. White, Suleiman A. Khan, Mike J. Mason, Muhammad Ammad-ud-din, Swapnil Potdar, Disha Malani, Heikki Kuusanmäki, Brian J. Druker, Caroline Heckman, Olli Kallioniemi, Stephen E. Kurtz, Kimmo Porkka, Cristina E. Tognon, Jeffrey W. Tyner, Tero Aittokallio, Krister Wennerberg, Justin Guinney
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/f6bd5ff98ce1490bb82d669c7207b895
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spelling	oai:doaj.org-article:f6bd5ff98ce1490bb82d669c7207b8952021-12-02T17:55:12ZBayesian multi-source regression and monocyte-associated gene expression predict BCL-2 inhibitor resistance in acute myeloid leukemia10.1038/s41698-021-00209-92397-768Xhttps://doaj.org/article/f6bd5ff98ce1490bb82d669c7207b8952021-07-01T00:00:00Zhttps://doi.org/10.1038/s41698-021-00209-9https://doaj.org/toc/2397-768XAbstract The FDA recently approved eight targeted therapies for acute myeloid leukemia (AML), including the BCL-2 inhibitor venetoclax. Maximizing efficacy of these treatments requires refining patient selection. To this end, we analyzed two recent AML studies profiling the gene expression and ex vivo drug response of primary patient samples. We find that ex vivo samples often exhibit a general sensitivity to (any) drug exposure, independent of drug target. We observe that this “general response across drugs” (GRD) is associated with FLT3-ITD mutations, clinical response to standard induction chemotherapy, and overall survival. Further, incorporating GRD into expression-based regression models trained on one of the studies improved their performance in predicting ex vivo response in the second study, thus signifying its relevance to precision oncology efforts. We find that venetoclax response is independent of GRD but instead show that it is linked to expression of monocyte-associated genes by developing and applying a multi-source Bayesian regression approach. The method shares information across studies to robustly identify biomarkers of drug response and is broadly applicable in integrative analyses.Brian S. WhiteSuleiman A. KhanMike J. MasonMuhammad Ammad-ud-dinSwapnil PotdarDisha MalaniHeikki KuusanmäkiBrian J. DrukerCaroline HeckmanOlli KallioniemiStephen E. KurtzKimmo PorkkaCristina E. TognonJeffrey W. TynerTero AittokallioKrister WennerbergJustin GuinneyNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Precision Oncology, Vol 5, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Brian S. White Suleiman A. Khan Mike J. Mason Muhammad Ammad-ud-din Swapnil Potdar Disha Malani Heikki Kuusanmäki Brian J. Druker Caroline Heckman Olli Kallioniemi Stephen E. Kurtz Kimmo Porkka Cristina E. Tognon Jeffrey W. Tyner Tero Aittokallio Krister Wennerberg Justin Guinney Bayesian multi-source regression and monocyte-associated gene expression predict BCL-2 inhibitor resistance in acute myeloid leukemia
description	Abstract The FDA recently approved eight targeted therapies for acute myeloid leukemia (AML), including the BCL-2 inhibitor venetoclax. Maximizing efficacy of these treatments requires refining patient selection. To this end, we analyzed two recent AML studies profiling the gene expression and ex vivo drug response of primary patient samples. We find that ex vivo samples often exhibit a general sensitivity to (any) drug exposure, independent of drug target. We observe that this “general response across drugs” (GRD) is associated with FLT3-ITD mutations, clinical response to standard induction chemotherapy, and overall survival. Further, incorporating GRD into expression-based regression models trained on one of the studies improved their performance in predicting ex vivo response in the second study, thus signifying its relevance to precision oncology efforts. We find that venetoclax response is independent of GRD but instead show that it is linked to expression of monocyte-associated genes by developing and applying a multi-source Bayesian regression approach. The method shares information across studies to robustly identify biomarkers of drug response and is broadly applicable in integrative analyses.
format	article
author	Brian S. White Suleiman A. Khan Mike J. Mason Muhammad Ammad-ud-din Swapnil Potdar Disha Malani Heikki Kuusanmäki Brian J. Druker Caroline Heckman Olli Kallioniemi Stephen E. Kurtz Kimmo Porkka Cristina E. Tognon Jeffrey W. Tyner Tero Aittokallio Krister Wennerberg Justin Guinney
author_facet	Brian S. White Suleiman A. Khan Mike J. Mason Muhammad Ammad-ud-din Swapnil Potdar Disha Malani Heikki Kuusanmäki Brian J. Druker Caroline Heckman Olli Kallioniemi Stephen E. Kurtz Kimmo Porkka Cristina E. Tognon Jeffrey W. Tyner Tero Aittokallio Krister Wennerberg Justin Guinney
author_sort	Brian S. White
title	Bayesian multi-source regression and monocyte-associated gene expression predict BCL-2 inhibitor resistance in acute myeloid leukemia
title_short	Bayesian multi-source regression and monocyte-associated gene expression predict BCL-2 inhibitor resistance in acute myeloid leukemia
title_full	Bayesian multi-source regression and monocyte-associated gene expression predict BCL-2 inhibitor resistance in acute myeloid leukemia
title_fullStr	Bayesian multi-source regression and monocyte-associated gene expression predict BCL-2 inhibitor resistance in acute myeloid leukemia
title_full_unstemmed	Bayesian multi-source regression and monocyte-associated gene expression predict BCL-2 inhibitor resistance in acute myeloid leukemia
title_sort	bayesian multi-source regression and monocyte-associated gene expression predict bcl-2 inhibitor resistance in acute myeloid leukemia
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/f6bd5ff98ce1490bb82d669c7207b895
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Bayesian multi-source regression and monocyte-associated gene expression predict BCL-2 inhibitor resistance in acute myeloid leukemia

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