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Cancer Cell. 2018 Oct 8;34(4):674-689.e8. doi: 10.1016/j.ccell.2018.08.014. Epub 2018 Sep 20.

Prospective Isolation and Characterization of Genetically and Functionally Distinct AML Subclones.

Author information

1
Department of Experimental Hematology, Cancer Research Centre Groningen (CRCG), University Medical Centre Groningen, University of Groningen, Hanzeplein 1, DA13, 9700 RB Groningen, the Netherlands.
2
Institute for Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, B15 2TT Birmingham, UK.
3
Department of Laboratory Medicine, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands.
4
Department of Pathology and Medical Biology, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands.
5
Evotec (München) GmbH, Am Klopferspitz 19a, 82152 Martinsried, Germany.
6
Janssen Research & Development, Turnhoutseweg 30, 2340 Beerse, Belgium.
7
Department of Experimental Hematology, Cancer Research Centre Groningen (CRCG), University Medical Centre Groningen, University of Groningen, Hanzeplein 1, DA13, 9700 RB Groningen, the Netherlands. Electronic address: j.j.schuringa@umcg.nl.

Abstract

Intra-tumor heterogeneity caused by clonal evolution is a major problem in cancer treatment. To address this problem, we performed label-free quantitative proteomics on primary acute myeloid leukemia (AML) samples. We identified 50 leukemia-enriched plasma membrane proteins enabling the prospective isolation of genetically distinct subclones from individual AML patients. Subclones differed in their regulatory phenotype, drug sensitivity, growth, and engraftment behavior, as determined by RNA sequencing, DNase I hypersensitive site mapping, transcription factor occupancy analysis, in vitro culture, and xenograft transplantation. Finally, we show that these markers can be used to identify and longitudinally track distinct leukemic clones in patients in routine diagnostics. Our study describes a strategy for a major improvement in stratifying cancer diagnosis and treatment.

KEYWORDS:

DNase I hypersensitive site (DHS); FLT3-ITD; NRAS; WT1; acute myeloid leukemia (AML); clonal heterogeneity; digital footprinting; genetically distinct subclones; plasma membrane (PM); proteome

PMID:
30245083
DOI:
10.1016/j.ccell.2018.08.014
[Indexed for MEDLINE]

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