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IDH1 as a Cooperating Mutation in AML Arising in the Context of Shwachman-Diamond Syndrome

Shwachman-Diamond syndrome (SDS) is a rare and systemic disease mostly caused by mutations in the SBDS gene and characterized by pancreatic insufficiency, skeletal abnormalities, and a bone marrow dysfunction. In addition, SDS patients are predisposed to develop myelodysplastic syndromes (MDS) and a...

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Autores principales: Mourad, Stéphanie, Bilodeau, Mélanie, Roussy, Mathieu, Laramée, Louise, Boulianne, Luc, Rouette, Alexandre, Jouan, Loubna, Gendron, Patrick, Duval, Michel, Teira, Pierre, Hébert, Josée, Bittencourt, Henrique, Pastore, Yves, Landry, Josette-Renée, Cellot, Sonia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702516/
https://www.ncbi.nlm.nih.gov/pubmed/31475115
http://dx.doi.org/10.3389/fonc.2019.00772
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author Mourad, Stéphanie
Bilodeau, Mélanie
Roussy, Mathieu
Laramée, Louise
Boulianne, Luc
Rouette, Alexandre
Jouan, Loubna
Gendron, Patrick
Duval, Michel
Teira, Pierre
Hébert, Josée
Bittencourt, Henrique
Pastore, Yves
Landry, Josette-Renée
Cellot, Sonia
author_facet Mourad, Stéphanie
Bilodeau, Mélanie
Roussy, Mathieu
Laramée, Louise
Boulianne, Luc
Rouette, Alexandre
Jouan, Loubna
Gendron, Patrick
Duval, Michel
Teira, Pierre
Hébert, Josée
Bittencourt, Henrique
Pastore, Yves
Landry, Josette-Renée
Cellot, Sonia
author_sort Mourad, Stéphanie
collection PubMed
description Shwachman-Diamond syndrome (SDS) is a rare and systemic disease mostly caused by mutations in the SBDS gene and characterized by pancreatic insufficiency, skeletal abnormalities, and a bone marrow dysfunction. In addition, SDS patients are predisposed to develop myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), typically during adulthood and associated with TP53 mutations. Although most SDS diagnoses are established in childhood, the nature and frequency of serial bone marrow cell investigations during the patients' lifetime remain a debatable topic. The precise molecular mechanisms leading to AML progression in SDS patients have not been fully elucidated because the patient cohorts are small and most disease monitoring is conducted using standard histological and cytogenetic approaches. Here we report a rare case of a patient with SDS who was diagnosed with AML at 5 years of age and survived. Intermittent neutropenia preceded the AML diagnostic but serial bone marrow monitoring according to the standard of care revealed no cytogenetic anomalies nor signs of clonal hematopoiesis. Using next generation sequencing approaches to find cytogenetically cryptic pathogenic mutations, we identified the cancer hotspot mutation c.394C>T/p.Arg132Cys in IDH1 with high variant allelic frequency in bone marrow cells, suggesting clonal expansion of a major leukemic clone karyotypically normal, in the SDS-associated AML. The mutation was somatic and likely occurred at the leukemic transformation stage, as it was not detected in a matched normal tissue nor in bone marrow smear prior to AML diagnosis. Gain-of-function mutations in IDH1, such as c.394C>T/p.Arg132Cys, create a neo-activity of isocitrate dehydrogenase 1 converting α-ketoglutarate into the oncometabolite D-2-hydroxyglutarate, inhibiting α-ketoglutarate-dependent enzymes, such as histone and DNA demethylases. Overall, our results suggest that along with previously described abnormalities such as TP53 mutations or monosomy7, 7q-, which are all absent in this patient, additional mechanisms including IDH1 mutations drive SDS-related AML and are likely associated with variable outcomes. Sensitive techniques complementary to standard cytogenetics, such as unbiased or targeted panel-based next generation sequencing approaches, warrant testing for monitoring of myelodysplasia, clonal hematopoiesis, and leukemia in the context SDS. Such analyses would also assist treatment decisions and allow to gain insight into the disease biology.
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spelling pubmed-67025162019-08-30 IDH1 as a Cooperating Mutation in AML Arising in the Context of Shwachman-Diamond Syndrome Mourad, Stéphanie Bilodeau, Mélanie Roussy, Mathieu Laramée, Louise Boulianne, Luc Rouette, Alexandre Jouan, Loubna Gendron, Patrick Duval, Michel Teira, Pierre Hébert, Josée Bittencourt, Henrique Pastore, Yves Landry, Josette-Renée Cellot, Sonia Front Oncol Oncology Shwachman-Diamond syndrome (SDS) is a rare and systemic disease mostly caused by mutations in the SBDS gene and characterized by pancreatic insufficiency, skeletal abnormalities, and a bone marrow dysfunction. In addition, SDS patients are predisposed to develop myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), typically during adulthood and associated with TP53 mutations. Although most SDS diagnoses are established in childhood, the nature and frequency of serial bone marrow cell investigations during the patients' lifetime remain a debatable topic. The precise molecular mechanisms leading to AML progression in SDS patients have not been fully elucidated because the patient cohorts are small and most disease monitoring is conducted using standard histological and cytogenetic approaches. Here we report a rare case of a patient with SDS who was diagnosed with AML at 5 years of age and survived. Intermittent neutropenia preceded the AML diagnostic but serial bone marrow monitoring according to the standard of care revealed no cytogenetic anomalies nor signs of clonal hematopoiesis. Using next generation sequencing approaches to find cytogenetically cryptic pathogenic mutations, we identified the cancer hotspot mutation c.394C>T/p.Arg132Cys in IDH1 with high variant allelic frequency in bone marrow cells, suggesting clonal expansion of a major leukemic clone karyotypically normal, in the SDS-associated AML. The mutation was somatic and likely occurred at the leukemic transformation stage, as it was not detected in a matched normal tissue nor in bone marrow smear prior to AML diagnosis. Gain-of-function mutations in IDH1, such as c.394C>T/p.Arg132Cys, create a neo-activity of isocitrate dehydrogenase 1 converting α-ketoglutarate into the oncometabolite D-2-hydroxyglutarate, inhibiting α-ketoglutarate-dependent enzymes, such as histone and DNA demethylases. Overall, our results suggest that along with previously described abnormalities such as TP53 mutations or monosomy7, 7q-, which are all absent in this patient, additional mechanisms including IDH1 mutations drive SDS-related AML and are likely associated with variable outcomes. Sensitive techniques complementary to standard cytogenetics, such as unbiased or targeted panel-based next generation sequencing approaches, warrant testing for monitoring of myelodysplasia, clonal hematopoiesis, and leukemia in the context SDS. Such analyses would also assist treatment decisions and allow to gain insight into the disease biology. Frontiers Media S.A. 2019-08-14 /pmc/articles/PMC6702516/ /pubmed/31475115 http://dx.doi.org/10.3389/fonc.2019.00772 Text en Copyright © 2019 Mourad, Bilodeau, Roussy, Laramée, Boulianne, Rouette, Jouan, Gendron, Duval, Teira, Hébert, Bittencourt, Pastore, Landry and Cellot. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Mourad, Stéphanie
Bilodeau, Mélanie
Roussy, Mathieu
Laramée, Louise
Boulianne, Luc
Rouette, Alexandre
Jouan, Loubna
Gendron, Patrick
Duval, Michel
Teira, Pierre
Hébert, Josée
Bittencourt, Henrique
Pastore, Yves
Landry, Josette-Renée
Cellot, Sonia
IDH1 as a Cooperating Mutation in AML Arising in the Context of Shwachman-Diamond Syndrome
title IDH1 as a Cooperating Mutation in AML Arising in the Context of Shwachman-Diamond Syndrome
title_full IDH1 as a Cooperating Mutation in AML Arising in the Context of Shwachman-Diamond Syndrome
title_fullStr IDH1 as a Cooperating Mutation in AML Arising in the Context of Shwachman-Diamond Syndrome
title_full_unstemmed IDH1 as a Cooperating Mutation in AML Arising in the Context of Shwachman-Diamond Syndrome
title_short IDH1 as a Cooperating Mutation in AML Arising in the Context of Shwachman-Diamond Syndrome
title_sort idh1 as a cooperating mutation in aml arising in the context of shwachman-diamond syndrome
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702516/
https://www.ncbi.nlm.nih.gov/pubmed/31475115
http://dx.doi.org/10.3389/fonc.2019.00772
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