Residual Disease in a Novel Xenograft Model of RUNX1-Mutated, Cytogenetically Normal Acute Myeloid Leukemia

Cytogenetically normal acute myeloid leukemia (CN-AML) patients harboring RUNX1 mutations have a dismal prognosis with anthracycline/cytarabine-based chemotherapy. We aimed to develop an in vivo model of RUNX1-mutated, CN-AML in which the nature of residual disease in this molecular disease subset c...

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Main Authors:	Sivagnanalingam, Umayal, Balys, Marlene, Eberhardt, Allison, Wang, Nancy, Myers, Jason R., Ashton, John M., Becker, Michael W., Calvi, Laura M., Mendler, Jason H.
Format:	Online
Language:	English
Published:	Public Library of Science 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4503761/

id	pubmed-4503761
recordtype	oai_dc
spelling	pubmed-45037612015-07-17 Residual Disease in a Novel Xenograft Model of RUNX1-Mutated, Cytogenetically Normal Acute Myeloid Leukemia Sivagnanalingam, Umayal Balys, Marlene Eberhardt, Allison Wang, Nancy Myers, Jason R. Ashton, John M. Becker, Michael W. Calvi, Laura M. Mendler, Jason H. Research Article Cytogenetically normal acute myeloid leukemia (CN-AML) patients harboring RUNX1 mutations have a dismal prognosis with anthracycline/cytarabine-based chemotherapy. We aimed to develop an in vivo model of RUNX1-mutated, CN-AML in which the nature of residual disease in this molecular disease subset could be explored. We utilized a well-characterized patient-derived, RUNX1-mutated CN-AML line (CG-SH). Tail vein injection of CG-SH into NOD scid gamma mice led to leukemic engraftment in the bone marrow, spleen, and peripheral blood within 6 weeks. Treatment of leukemic mice with anthracycline/cytarabine-based chemotherapy resulted in clearance of disease from the spleen and peripheral blood, but persistence of disease in the bone marrow as assessed by flow cytometry and secondary transplantation. Whole exome sequencing of CG-SH revealed mutations in ASXL1, CEBPA, GATA2, and SETBP1, not previously reported. We conclude that CG-SH xenografts are a robust, reproducible in vivo model of CN-AML in which to explore mechanisms of chemotherapy resistance and novel therapeutic approaches. Public Library of Science 2015-07-15 /pmc/articles/PMC4503761/ /pubmed/26177509 http://dx.doi.org/10.1371/journal.pone.0132375 Text en © 2015 Sivagnanalingam et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Sivagnanalingam, Umayal Balys, Marlene Eberhardt, Allison Wang, Nancy Myers, Jason R. Ashton, John M. Becker, Michael W. Calvi, Laura M. Mendler, Jason H.
spellingShingle	Sivagnanalingam, Umayal Balys, Marlene Eberhardt, Allison Wang, Nancy Myers, Jason R. Ashton, John M. Becker, Michael W. Calvi, Laura M. Mendler, Jason H. Residual Disease in a Novel Xenograft Model of RUNX1-Mutated, Cytogenetically Normal Acute Myeloid Leukemia
author_facet	Sivagnanalingam, Umayal Balys, Marlene Eberhardt, Allison Wang, Nancy Myers, Jason R. Ashton, John M. Becker, Michael W. Calvi, Laura M. Mendler, Jason H.
author_sort	Sivagnanalingam, Umayal
title	Residual Disease in a Novel Xenograft Model of RUNX1-Mutated, Cytogenetically Normal Acute Myeloid Leukemia
title_short	Residual Disease in a Novel Xenograft Model of RUNX1-Mutated, Cytogenetically Normal Acute Myeloid Leukemia
title_full	Residual Disease in a Novel Xenograft Model of RUNX1-Mutated, Cytogenetically Normal Acute Myeloid Leukemia
title_fullStr	Residual Disease in a Novel Xenograft Model of RUNX1-Mutated, Cytogenetically Normal Acute Myeloid Leukemia
title_full_unstemmed	Residual Disease in a Novel Xenograft Model of RUNX1-Mutated, Cytogenetically Normal Acute Myeloid Leukemia
title_sort	residual disease in a novel xenograft model of runx1-mutated, cytogenetically normal acute myeloid leukemia
description	Cytogenetically normal acute myeloid leukemia (CN-AML) patients harboring RUNX1 mutations have a dismal prognosis with anthracycline/cytarabine-based chemotherapy. We aimed to develop an in vivo model of RUNX1-mutated, CN-AML in which the nature of residual disease in this molecular disease subset could be explored. We utilized a well-characterized patient-derived, RUNX1-mutated CN-AML line (CG-SH). Tail vein injection of CG-SH into NOD scid gamma mice led to leukemic engraftment in the bone marrow, spleen, and peripheral blood within 6 weeks. Treatment of leukemic mice with anthracycline/cytarabine-based chemotherapy resulted in clearance of disease from the spleen and peripheral blood, but persistence of disease in the bone marrow as assessed by flow cytometry and secondary transplantation. Whole exome sequencing of CG-SH revealed mutations in ASXL1, CEBPA, GATA2, and SETBP1, not previously reported. We conclude that CG-SH xenografts are a robust, reproducible in vivo model of CN-AML in which to explore mechanisms of chemotherapy resistance and novel therapeutic approaches.
publisher	Public Library of Science
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4503761/
_version_	1613248343045046272

Residual Disease in a Novel Xenograft Model of RUNX1-Mutated, Cytogenetically Normal Acute Myeloid Leukemia

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