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

Abstract

Leukaemias and other cancers possess a rare population of cells capable of the limitless self-renewal necessary for cancer initiation and maintenance. 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 self-renewal, 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.

Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model

“…However, by transferring AML into recipient mice from sorted phenotypic GMP, we confirmed that LIC potential is retained in a population of committed progenitors similar to previous work, which demonstrated the potential to initiate leukemia from a GMP-like cell. 18,38 Comparing cohorts that received populations from KL or KLI, we observed a shorter latency of AML development in recipients that were transplanted with the respective population from KLI mice indicating a proliferative effect of FLT3 ITD on the blast cells.…”

Flow cytometric maturity score as a novel prognostic parameter in patients with acute myeloid leukemia

“…Since these LSC -particularly in their dormant stage -may survive treatment and give rise to subsequent relapse [19,[28][29][30][31][32][33][34][35][36][37][38][39]. The latter idea is supported by a recent study showing that a higher level of putative CD34 + /CD38 --LSC is associated with a worse prognosis [40].…”

Hox genes in hematopoiesis and leukemogenesis

“…Support for this hypothesis comes from multiple murine studies demonstrating that purified committed hematopoietic progenitors, with limited self-renewal capacities, engineered to overexpress the Hox gene regulators MLL-AF9 (Krivtsov et al, 2006), MLL-ENL (Cozzio et al, 2003) or MLL-GAS7 (So et al, 2004) can be transformed into LSCs. In the latter study, leukemic transformation of committed progenitors by MLL-GAS7 was Hoxa7 or Hoxa9-independent.…”