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Exp Hematol. 2017 Sep;53:48-58. doi: 10.1016/j.exphem.2017.05.007. Epub 2017 Jun 8.

Whole-genome analysis reveals unexpected dynamics of mutant subclone development in a patient with JAK2-V617F-positive chronic myeloid leukemia.

Author information

1
Institut National de la Santé et de la Recherche Médicale (INSERM) U935, Villejuif, France; Service d'Hématologie Biologique, Institut Federatif d'Hematologie Interpôle Paris Sud-IFHIPS (AP-HP) Kremlin Bicêtre, Paris, France; Université Paris-Sud, Faculté de Médecine Kremlin Bicêtre, and INSERM UMS 33, Villejuif, France.
2
Institut National de la Santé et de la Recherche Médicale (INSERM) U935, Villejuif, France.
3
Institut National de la Santé et de la Recherche Médicale (INSERM) U935, Villejuif, France; Human Pluripotent Stem Cell Core Facility, ESTeam Paris Sud-INGESTEM, Villejuif, France.
4
Institut National de la Santé et de la Recherche Médicale (INSERM) U935, Villejuif, France; Human Pluripotent Stem Cell Core Facility, ESTeam Paris Sud-INGESTEM, Villejuif, France; Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France.
5
Human Pluripotent Stem Cell Core Facility, ESTeam Paris Sud-INGESTEM, Villejuif, France.
6
Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France; AP-HP, Hôpital Européen Georges Pompidou, Service d'Hématologie Biologique, Paris, France.
7
Université Paris-Sud, Faculté de Médecine Kremlin Bicêtre, and INSERM UMS 33, Villejuif, France.
8
University of British Columbia, Centre for High-Throughput Biology and Department of Microbiology & Immunology, Vancouver, BC, Canada.
9
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
10
University of British Columbia, Centre for High-Throughput Biology and Department of Microbiology & Immunology, Vancouver, BC, Canada; Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
11
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada; Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, Canada.
12
Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
13
Institut National de la Santé et de la Recherche Médicale (INSERM) U935, Villejuif, France; Service d'Hématologie Biologique, Institut Federatif d'Hematologie Interpôle Paris Sud-IFHIPS (AP-HP) Kremlin Bicêtre, Paris, France; Université Paris-Sud, Faculté de Médecine Kremlin Bicêtre, and INSERM UMS 33, Villejuif, France; Human Pluripotent Stem Cell Core Facility, ESTeam Paris Sud-INGESTEM, Villejuif, France.
14
Institut National de la Santé et de la Recherche Médicale (INSERM) U935, Villejuif, France; Service d'Hématologie Biologique, Institut Federatif d'Hematologie Interpôle Paris Sud-IFHIPS (AP-HP) Kremlin Bicêtre, Paris, France; Université Paris-Sud, Faculté de Médecine Kremlin Bicêtre, and INSERM UMS 33, Villejuif, France; Human Pluripotent Stem Cell Core Facility, ESTeam Paris Sud-INGESTEM, Villejuif, France. Electronic address: turviv33@gmail.com.

Abstract

We report here the first use of whole-genome sequencing (WGS) to examine the initial clonal dynamics in an unusual patient with chronic myeloid leukemia (CML), who presented in chronic phase (CP) with doubly marked BCR-ABL1+/JAK2V617F-mutant cells and, over a 9-year period, progressed into an accelerated phase (AP) and then terminal blast phase (BP). WGS revealed that the diagnostic cells also contained mutations in ASXL1, SEC23B, MAD1L1, and RREB1 as well as 12,000 additional uncommon DNA variants. WGS of endothelial cells generated from circulating precursors revealed many of these were shared with the CML clone. Surprisingly, WGS of induced pluripotent stem cells (iPSCs) derived from the AP cells revealed only six additional coding somatic mutations, despite retention by the hematopoietic progeny of the parental AP cell levels of BCR-ABL1 expression and sensitivity to imatinib and pimozide. Limited analysis of BP cells revealed independent subclonal progression to homozygosity of the MAD1L1 and RREB1 variants. MAD1L1 and SEC23B mutations were also identified in 2 of 101 cases of myeloproliferative neoplasms, but not in 42 healthy subjects. These findings challenge historic concepts of clonal evolution in CML.

PMID:
28602946
DOI:
10.1016/j.exphem.2017.05.007
[Indexed for MEDLINE]

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