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

A. V. Krivtsov, Maria 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

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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 1 2013
Externally publishedYes

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Acute Myeloid Leukemia
Leukemia
Hematopoietic Stem Cells
Granulocyte-Macrophage Progenitor Cells
Transcriptome
Myeloid-Lymphoid Leukemia Protein
Clone Cells
Gene Expression
Myeloid Cells
Epigenomics
Stem Cells
Drug Therapy

Keywords

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

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

Krivtsov, A. V., Figueroa, M., Sinha, A. U., Stubbs, M. C., Feng, Z., Valk, P. J. 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

Cell of origin determines clinically relevant subtypes of MLL-rearranged AML. / Krivtsov, A. V.; Figueroa, Maria; 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.

In: Leukemia, Vol. 27, No. 4, 01.04.2013, p. 852-860.

Research output: Contribution to journalArticle

Krivtsov, AV, Figueroa, M, Sinha, AU, Stubbs, MC, Feng, Z, Valk, PJM, Delwel, R, Döhner, K, Bullinger, L, Kung, AL, Melnick, AM & Armstrong, SA 2013, 'Cell of origin determines clinically relevant subtypes of MLL-rearranged AML', Leukemia, vol. 27, no. 4, pp. 852-860. https://doi.org/10.1038/leu.2012.363
Krivtsov AV, Figueroa M, Sinha AU, Stubbs MC, Feng Z, Valk PJM et al. Cell of origin determines clinically relevant subtypes of MLL-rearranged AML. Leukemia. 2013 Apr 1;27(4):852-860. https://doi.org/10.1038/leu.2012.363
Krivtsov, A. V. ; Figueroa, Maria ; 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. / Cell of origin determines clinically relevant subtypes of MLL-rearranged AML. In: Leukemia. 2013 ; Vol. 27, No. 4. pp. 852-860.
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