Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9

doi:10.1038/nature04980; Nature. 2006 Aug 17;442(7104):818-22. Epub 2006 Jul 16. Published: 2006.08.16

Andrei Krivtsov, David Twomey, Zhaohui Feng, Matthew C. Stubbs, Yingzi Wang, Joerg Faber, Jason E. Levine, Jing Wang, William C. Hahn, D. Gary Gilliland, Todd R. Golub, Scott A. Armstrong

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Abstract

Leukaemias and other cancers possess a rare population of cells capable of the limitless self-renewal necessary for cancer initiation and maintenance1-7. Eradication of these cancer stem cells is probably a critical part of any successful anti-cancer therapy, and may explain why conventional cancer therapies are often effective in reducing tumour burden, but are only rarely curative. Given that both normal and cancer stem cells are capable of selfrenewal, the extent to which cancer stem cells resemble normal tissue stem cells is a critical issue if targeted therapies are to be developed. However, it remains unclear whether cancer stem cells must be phenotypically similar to normal tissue stem cells or whether they can retain the identity of committed progenitors. Here we show that leukaemia stem cells (LSC) can maintain the global identity of the progenitor from which they arose while activating a limited stem-cell- or self-renewal-associated programme. We isolated LSC from leukaemias initiated in committed granulocyte macrophage progenitors through introduction of the MLL-AF9 fusion protein encoded by the t(9;11)(p22;q23). The LSC were capable of transferring leukaemia to secondary recipient mice when only four cells were transferred, and possessed an immunophenotype and global gene expression profile very similar to that of normal granulocyte macrophage progenitors. However, a subset of genes highly expressed in normal haematopoietic stem cells was re-activated in LSC. LSC can thus be generated from committed progenitors without widespread reprogramming of gene expression, and a leukaemia self-renewal-associated signature is activated in the process. Our findings define progression from normal progenitor to cancer stem cell, and suggest that targeting a self-renewal programme expressed in an abnormal context may be possible.

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Supplemental Data

Description Link/Filename
Normal Progenitor And Leukemic Samples Normals_Leu.gct
MLL-AF9 Immediate Samples MLL_AF9.gct
HSC Signature compared to other normal progenitors. http://www.broadinstitute.org/mpr/publications/projects/Leukemia/
Metric:SNR; # significant genes 1334 (FDR<=0.02) HSC_FDR002.gct
Leukemic GMP Signature. filtering:max-min=80;max/min=2.5 http://www.broadinstitute.org/mpr/publications/projects/Leukemia/
SNR;592 genes;p-value<=0.01;FDR<=0.023 leuGMP.gct
Self-renewal associated signature. http://www.broadinstitute.org/mpr/publications/projects/Leukemia/
Filtering: max-min=80;max/min=2.5 Normals_Leu.threshold_FDR01.gct
Metric:SNR;420 significant probesets; p-value<=0.001, FDR <=0.01 http://www.broadinstitute.org/mpr/publications/projects/Leukemia/
Self-renewal associated signature - Down. http://www.broadinstitute.org/mpr/publications/projects/Leukemia/
Filtering: max-min=80;max/min=2.5 300_HSCLeu_dn_0306.gct
Metric:SNR;302 significant probe sets; p-value<=0.001, FDR<=0.01 http://www.broadinstitute.org/mpr/publications/projects/Leukemia/
Zip of CEL Files nature.zip
Sample Key SampleKey.xls