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Identification of novel MECOM gene fusion and personalized therapeutic targets through integrative clinical sequencing in secondary acute myeloid leukemia in a patient with severe congenital neutropenia: a case report and literature review

Severe congenital neutropenia (SCN) is a rare hematologic disorder characterized by defective myelopoiesis and a high incidence of malignant transformation to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). SCN patients who develop MDS/AML have excessive toxicities to traditional ch...

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Autores principales: Connelly, James A., Mody, Rajen J., Wu, Yi-Mi, Robinson, Dan R., Lonigro, Robert J., Vats, Pankaj, Rabban, Erica, Anderson, Bailey, Walkovich, Kelly
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880254/
https://www.ncbi.nlm.nih.gov/pubmed/29572239
http://dx.doi.org/10.1101/mcs.a002204
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author Connelly, James A.
Mody, Rajen J.
Wu, Yi-Mi
Robinson, Dan R.
Lonigro, Robert J.
Vats, Pankaj
Rabban, Erica
Anderson, Bailey
Walkovich, Kelly
author_facet Connelly, James A.
Mody, Rajen J.
Wu, Yi-Mi
Robinson, Dan R.
Lonigro, Robert J.
Vats, Pankaj
Rabban, Erica
Anderson, Bailey
Walkovich, Kelly
author_sort Connelly, James A.
collection PubMed
description Severe congenital neutropenia (SCN) is a rare hematologic disorder characterized by defective myelopoiesis and a high incidence of malignant transformation to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). SCN patients who develop MDS/AML have excessive toxicities to traditional chemotherapy, and safer therapies are needed to improve overall survival in this population. In this report, we outline the use of a prospective integrative clinical sequencing trial (PEDS-MIONCOSEQ) in a patient with SCN and AML to help identify oncogenic targets for less toxic agents. Integrative sequencing identified two somatic cis-mutations in the colony stimulating factor 3 receptor (CSF3R) gene, a p.T640N mutation in the transmembrane region and a p.Q768* truncation mutation in the cytoplasmic domain. A somatic mutation p.H105Y, in the runt homology domain (RHD) of runt-related transcription factor 1 (RUNX1), was also identified. In addition, sequencing discovered a unique in-frame EIF4A2-MECOM (MDS1 and ectopic viral integration site 1 complex) chromosomal translocation with high MECOM expression. His mutations in CSF3R served as potential targets for tyrosine kinase inhibition and therefore provided an avenue to avoid more harmful therapy. This study highlights the utility of integrative clinical sequencing in SCN patients who develop leukemia and outlines a strategy on how to approach these patients in a future clinical sequencing trial to improve historically poor outcomes. A thorough review of leukemia in SCN and the role of CSF3R mutations in oncologic therapy are provided to support a new strategy on how to approach MDS/AML in SCN.
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spelling pubmed-58802542018-04-13 Identification of novel MECOM gene fusion and personalized therapeutic targets through integrative clinical sequencing in secondary acute myeloid leukemia in a patient with severe congenital neutropenia: a case report and literature review Connelly, James A. Mody, Rajen J. Wu, Yi-Mi Robinson, Dan R. Lonigro, Robert J. Vats, Pankaj Rabban, Erica Anderson, Bailey Walkovich, Kelly Cold Spring Harb Mol Case Stud Research Report Severe congenital neutropenia (SCN) is a rare hematologic disorder characterized by defective myelopoiesis and a high incidence of malignant transformation to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). SCN patients who develop MDS/AML have excessive toxicities to traditional chemotherapy, and safer therapies are needed to improve overall survival in this population. In this report, we outline the use of a prospective integrative clinical sequencing trial (PEDS-MIONCOSEQ) in a patient with SCN and AML to help identify oncogenic targets for less toxic agents. Integrative sequencing identified two somatic cis-mutations in the colony stimulating factor 3 receptor (CSF3R) gene, a p.T640N mutation in the transmembrane region and a p.Q768* truncation mutation in the cytoplasmic domain. A somatic mutation p.H105Y, in the runt homology domain (RHD) of runt-related transcription factor 1 (RUNX1), was also identified. In addition, sequencing discovered a unique in-frame EIF4A2-MECOM (MDS1 and ectopic viral integration site 1 complex) chromosomal translocation with high MECOM expression. His mutations in CSF3R served as potential targets for tyrosine kinase inhibition and therefore provided an avenue to avoid more harmful therapy. This study highlights the utility of integrative clinical sequencing in SCN patients who develop leukemia and outlines a strategy on how to approach these patients in a future clinical sequencing trial to improve historically poor outcomes. A thorough review of leukemia in SCN and the role of CSF3R mutations in oncologic therapy are provided to support a new strategy on how to approach MDS/AML in SCN. Cold Spring Harbor Laboratory Press 2018-04 /pmc/articles/PMC5880254/ /pubmed/29572239 http://dx.doi.org/10.1101/mcs.a002204 Text en © 2018 Connelly et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/) , which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.
spellingShingle Research Report
Connelly, James A.
Mody, Rajen J.
Wu, Yi-Mi
Robinson, Dan R.
Lonigro, Robert J.
Vats, Pankaj
Rabban, Erica
Anderson, Bailey
Walkovich, Kelly
Identification of novel MECOM gene fusion and personalized therapeutic targets through integrative clinical sequencing in secondary acute myeloid leukemia in a patient with severe congenital neutropenia: a case report and literature review
title Identification of novel MECOM gene fusion and personalized therapeutic targets through integrative clinical sequencing in secondary acute myeloid leukemia in a patient with severe congenital neutropenia: a case report and literature review
title_full Identification of novel MECOM gene fusion and personalized therapeutic targets through integrative clinical sequencing in secondary acute myeloid leukemia in a patient with severe congenital neutropenia: a case report and literature review
title_fullStr Identification of novel MECOM gene fusion and personalized therapeutic targets through integrative clinical sequencing in secondary acute myeloid leukemia in a patient with severe congenital neutropenia: a case report and literature review
title_full_unstemmed Identification of novel MECOM gene fusion and personalized therapeutic targets through integrative clinical sequencing in secondary acute myeloid leukemia in a patient with severe congenital neutropenia: a case report and literature review
title_short Identification of novel MECOM gene fusion and personalized therapeutic targets through integrative clinical sequencing in secondary acute myeloid leukemia in a patient with severe congenital neutropenia: a case report and literature review
title_sort identification of novel mecom gene fusion and personalized therapeutic targets through integrative clinical sequencing in secondary acute myeloid leukemia in a patient with severe congenital neutropenia: a case report and literature review
topic Research Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880254/
https://www.ncbi.nlm.nih.gov/pubmed/29572239
http://dx.doi.org/10.1101/mcs.a002204
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