title: Hematopoietic Differentiation Is Required for Initiation of Acute Myeloid Leukemia.
abstract: Mutations in acute myeloid leukemia (AML)-associated oncogenes often arise in hematopoietic stem cells (HSCs) and promote acquisition of leukemia stem cell (LSC) phenotypes. However, as LSCs often share features of lineage-restricted progenitors, the relative contribution of differentiation status to LSC transformation is unclear. Using murine MLL-AF9 and MOZ-TIF2 AML models, we show that myeloid differentiation to granulocyte macrophage progenitors (GMPs) is critical for LSC generation. Disrupting GMP formation by deleting the lineage-restricted transcription factor C/EBPa blocked normal granulocyte formation and prevented initiation of AML. However, restoring myeloid differentiation in C/EBPa mutants with inflammatory cytokines reestablished AML transformation capacity. Genomic analyses of GMPs, including gene expression and H3K79me2 profiling in conjunction with ATAC-seq, revealed a permissive genomic environment for activation of a minimal transcription program shared by GMPs and LSCs. Together, these findings show that myeloid differentiation is a prerequisite for LSC formation and AML development, providing insights for therapeutic development.
authors.affiliation: Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Ye
authors.affiliation: Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Cancer Science Institute, National University of Singapore, Singapore, 117599.
authors.forename: Henry
authors.initials: H
authors.lastname: Yang
authors.affiliation: Cancer Biology and Genetics Program and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, NY 10065, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Koche
authors.affiliation: Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA; Division of Hematology and Hemostaseology, Comprehensive Cancer Centre Vienna, Medical University of Vienna, A-1090 Vienna, Austria.
authors.forename: Philipp B
authors.initials: PB
authors.lastname: Staber
authors.affiliation: Cancer Biology and Genetics Program and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, NY 10065, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Cusan
authors.affiliation: Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA; Institute of Biomedical Technologies, National Research Council, Pisa 56124, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Levantini
authors.affiliation: Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Welner
authors.affiliation: Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA; Department of Hematology/Oncology, University Hospital Erlangen, 91054 Erlangen, Germany.
authors.forename: Christian S
authors.initials: CS
authors.lastname: Bach
authors.affiliation: Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Junyan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Cancer Biology and Genetics Program and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, NY 10065, USA.
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Krivtsov
authors.affiliation: Cancer Biology and Genetics Program and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, NY 10065, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Armstrong
authors.affiliation: Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA; Cancer Science Institute, National University of Singapore, Singapore, 117599. Electronic address: daniel.tenen@nus.edu.sg.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Tenen
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D004195:Disease Models, Animal; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout
chemical_list: D016178:Granulocyte-Macrophage Colony-Stimulating Factor