title: Leukaemia cell of origin identified by chromatin landscape of bulk tumour cells.
abstract: The precise identity of a tumour's cell of origin can influence disease prognosis and outcome. Methods to reliably define tumour cell of origin from primary, bulk tumour cell samples has been a challenge. Here we use a well-defined model of MLL-rearranged acute myeloid leukaemia (AML) to demonstrate that transforming haematopoietic stem cells (HSCs) and multipotent progenitors results in more aggressive AML than transforming committed progenitor cells. Transcriptome profiling reveals a gene expression signature broadly distinguishing stem cell-derived versus progenitor cell-derived AML, including genes involved in immune escape, extravasation and small GTPase signal transduction. However, whole-genome profiling of open chromatin reveals precise and robust biomarkers reflecting each cell of origin tested, from bulk AML tumour cell sampling. We find that bulk AML tumour cells exhibit distinct open chromatin loci that reflect the transformed cell of origin and suggest that open chromatin patterns may be leveraged as prognostic signatures in human AML.
authors.affiliation: The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, Connecticut 06032, USA.
authors.forename: Joshy
authors.identifier: 0000-0002-9405-4856
authors.initials: J
authors.lastname: George
authors.affiliation: The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, Connecticut 06032, USA.
authors.forename: Asli
authors.initials: A
authors.lastname: Uyar
authors.affiliation: The Jackson Laboratory for Mammalian Genetics, 600 Main Street, Bar Harbor, Maine 04609, USA.
authors.forename: Kira
authors.initials: K
authors.lastname: Young
authors.affiliation: The Jackson Laboratory for Mammalian Genetics, 600 Main Street, Bar Harbor, Maine 04609, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Kuffler
authors.affiliation: The Jackson Laboratory for Mammalian Genetics, 600 Main Street, Bar Harbor, Maine 04609, USA.
authors.forename: Kaiden
authors.initials: K
authors.lastname: Waldron-Francis
authors.affiliation: The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, Connecticut 06032, USA.
authors.forename: Eladio
authors.identifier: 0000-0001-5548-5795
authors.initials: E
authors.lastname: Marquez
authors.affiliation: The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, Connecticut 06032, USA.
authors.forename: Duygu
authors.identifier: 0000-0002-9772-3066
authors.initials: D
authors.lastname: Ucar
authors.affiliation: The Jackson Laboratory for Mammalian Genetics, 600 Main Street, Bar Harbor, Maine 04609, USA.
authors.forename: Jennifer J
authors.identifier: 0000-0002-7636-9504
authors.initials: JJ
authors.lastname: Trowbridge
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D042002:Chromatin Assembly and Disassembly; D044127:Epigenesis, Genetic; D005260:Female; D057809:HEK293 Cells; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000209:etiology* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D039902:Multipotent Stem Cells / Q000378:metabolism; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D059467:Transcriptome
chemical_list: C474558:MLL-AF9 fusion protein, human; C551356:MLL-AF9 fusion protein, mouse; D015514:Oncogene Proteins, Fusion; D051788:Myeloid-Lymphoid Leukemia Protein