Page 122 - 2020_01-Haematologica-web

Ferrata Storti Foundation
Haematologica 2020 Volume 105(1):112-123
Myelodysplastic/Myeloproliferative Neoplasms
Multilayer intraclonal heterogeneity in chronic myelomonocytic leukemia
Allan Beke,1,2,* Lucie Laplane,1,3,* Julie Riviere,1 Qin Yang,4 Miguel Torres- Martin,4 Thibault Dayris,5 Philippe Rameau,5 Veronique Saada,6 Chrystèle Bilhou-Nabera,7 Ana Hurtado,8 Larissa Lordier,1,5 William Vainchenker,1 Maria E. Figueroa,4,9 Nathalie Droin1,2 and Eric Solary1,2,10
1INSERM U1170, Gustave Roussy Cancer Center, Villejuif, France; 2Université Paris-Sud, Faculté de Médecine, Le Kremlin-Bicêtre, France; 3CNRS UMR8590, IHPST, Université Paris 1 Panthéon-Sorbonne, Paris, France; 4Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA; 5CNRS 3655 & INSERM US23, AMMICa, Gustave Roussy Cancer Center, Villejuif, France; 6Department of Biopathology, Gustave Roussy Cancer Center, Villejuif, France; 7Service d’Hématologie Biologique, Hôpital Saint-Antoine, Paris, France; 8Hematology and Medical Oncology Department, Hospital Morales Meseguer, IMIB, Murcia, Spain; 9Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA and 10Department of Hematology, Gustave Roussy Cancer Center, Villejuif, France
*AB and LL contributed equally to this study
ABSTRACT
The functional diversity of cells that compose myeloid malignancies, i.e., the respective roles of genetic and epigenetic heterogeneity in this diversity, remains poorly understood. This question is addressed in chronic myelomonocytic leukemia, a myeloid neoplasm in which clinical diversity contrasts with limited genetic heterogeneity. To generate induced pluripotent stem cell clones, we reprogrammed CD34+ cells collected from a patient with a chronic myelomonocytic leukemia in which whole exome sequencing of peripheral blood monocyte DNA had identified 12 gene mutations, including a mutation in KDM6A and two heterozygous muta- tions in TET2 in the founding clone and a secondary KRAS(G12D) muta- tion. CD34+ cells from an age-matched healthy donor were also repro- grammed. We captured a part of the genetic heterogeneity observed in the patient, i.e. we analyzed five clones with two genetic backgrounds, without and with the KRAS(G12D) mutation. Hematopoietic differentiation of these clones recapitulated the main features of the patient’s disease, includ- ing overproduction of granulomonocytes and dysmegakaryopoiesis. These analyses also disclosed significant discrepancies in the behavior of hematopoietic cells derived from induced pluripotent stem cell clones with similar genetic background, correlating with limited epigenetic changes. These analyses suggest that, beyond the coding mutations, several levels of intraclonal heterogeneity may participate in the yet unexplained clinical heterogeneity of the disease.
Introduction
Intratumoral heterogeneity is a major tenet of cancer biology. A tumor clone emerges from a single cell that has acquired one or several somatic mutations. Additional driver events that occur in individual daughter cells generate tumor sub- clones, each being endowed with specific functional properties and fitness.1 This intraclonal genetic heterogeneity may not explain all the functional heterogeneity among individual cells within a tumor clone. Epigenetic variation also contributes to the heterogeneity of cells that form a tumor.2,3
Chronic myelomonocytic leukemia (CMML) is a neoplastic disease whose limit- ed genetic heterogeneity contrasts with its clinical diversity.4 CMML is defined by a persistent clonal monocytosis, with or without dysplasia.5 The mutational land- scape contains a small number of somatic mutations in DNA methylation, histone
Correspondence:
ERIC SOLARY
eric.solary@gustaveroussy.fr
Received: October 4, 2018. Accepted: April 30, 2019. Pre-published: May 2, 2019.
doi:10.3324/haematol.2018.208488
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/1/112
©2020 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
112
haematologica | 2020; 105(1)
ARTICLE