Cell of origin determines clinically relevant subtypes of MLL-rearranged AML

A. V. Krivtsov, M. E. Figueroa, A. U. Sinha, M. C. Stubbs, Z. Feng, P. J.M. Valk, R. Delwel, K. Döhner, L. Bullinger, A. L. Kung, A. M. Melnick, S. A. Armstrong

Research output: Contribution to journalArticle

102 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)852-860
Number of pages9
JournalLeukemia
Volume27
Issue number4
DOIs
StatePublished - Apr 2013

Keywords

  • DNA methylation
  • MLL
  • cell of origin
  • chemotherapy
  • drug resistance
  • gene expression

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Cell of origin determines clinically relevant subtypes of MLL-rearranged AML'. Together they form a unique fingerprint.

  • Cite this

    Krivtsov, A. V., Figueroa, M. E., Sinha, A. U., Stubbs, M. C., Feng, Z., Valk, P. J. M., Delwel, R., Döhner, K., Bullinger, L., Kung, A. L., Melnick, A. M., & Armstrong, S. A. (2013). Cell of origin determines clinically relevant subtypes of MLL-rearranged AML. Leukemia, 27(4), 852-860. https://doi.org/10.1038/leu.2012.363