title: Cell of origin determines clinically relevant subtypes of MLL-rearranged AML.
abstract: Mixed lineage leukemia (MLL)-fusion proteins can induce acute myeloid leukemias (AMLs) from either hematopoietic stem cells (HSCs) or granulocyte-macrophage progenitors (GMPs), but it remains unclear whether the cell of origin influences the biology of the resultant leukemia. MLL-AF9-transduced single HSCs or GMPs could be continuously replated, but HSC-derived clones were more likely than GMP-derived clones to initiate AML in mice. Leukemia stem cells derived from either HSCs or GMPs had a similar immunophenotype consistent with a maturing myeloid cell (LGMP). Gene expression analyses demonstrated that LGMP inherited gene expression programs from the cell of origin including high-level Evi-1 expression in HSC-derived LGMP. The gene expression signature of LGMP derived from HSCs was enriched in poor prognosis human MLL-rearranged AML in three independent data sets. Moreover, global 5'-mC levels were elevated in HSC-derived leukemias as compared with GMP-derived leukemias. This mirrored a difference seen in 5'-mC between MLL-rearranged human leukemias that are either EVI1 positive or EVI1 negative. Finally, HSC-derived leukemias were more resistant to chemotherapy than GMP-derived leukemias. These data demonstrate that the cell of origin influences the gene expression profile, the epigenetic state and the drug response in AML, and that these differences can account for clinical heterogeneity within a molecularly defined group of leukemias.
authors.affiliation: Division of Hematology/Oncology, Children's Hospital, Boston, MA, USA.
authors.forename: A V
authors.initials: AV
authors.lastname: Krivtsov
authors.forename: M E
authors.initials: ME
authors.lastname: Figueroa
authors.forename: A U
authors.initials: AU
authors.lastname: Sinha
authors.forename: M C
authors.initials: MC
authors.lastname: Stubbs
authors.forename: Z
authors.initials: Z
authors.lastname: Feng
authors.forename: P J M
authors.initials: PJ
authors.lastname: Valk
authors.forename: R
authors.initials: R
authors.lastname: Delwel
authors.forename: K
authors.initials: K
authors.lastname: Döhner
authors.forename: L
authors.initials: L
authors.lastname: Bullinger
authors.forename: A L
authors.initials: AL
authors.lastname: Kung
authors.forename: A M
authors.initials: AM
authors.lastname: Melnick
authors.forename: S A
authors.initials: SA
authors.lastname: Armstrong
mesh_terms: D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D003561:Cytarabine / Q000494:pharmacology; D020869:Gene Expression Profiling; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; C497422:KMT2A protein, human; D003561:Cytarabine; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase