Continuous MLL-ENL expression is necessary to establish a "Hox code" and maintain immortalization of hematopoietic progenitor cells

Sarah J. Horton, David G. Grier, Glenda J. McGonigle, Alexander Thompson, Michelle Morrow, Inusha De Silva, Dale A. Moulding, Dimitris Kioussis, Terence R.J. Lappin, Hugh J.M. Brady, Owen Williams

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61 Citations (Scopus)

Abstract

The t[(11;19)(p22;q23)] translocation, which gives rise to the MLL-ENL fusion protein, is commonly found in infant acute leukemias of both the myeloid and lymphoid lineage. To investigate the molecular mechanism of immortalization by MLL-ENL we established a Tet-regulatable system of MLL-ENL expression in primary hematopoietic progenitor cells. Immortalized myeloid cell lines were generated, which are dependent on continued MLL-ENL expression for their survival and proliferation. These cells either terminally differentiate or die when MLL-ENL expression is turned off with doxycycline. The expression profile of all 39 murine Hox genes was analyzed in these cells by real-time quantitative PCR. This analysis showed that loss of MLL-ENL was accompanied by a reduction in the expression of multiple Hoxa genes. By comparing these changes with Hox gene expression in cells induced to differentiate with granulocyte colony-stimulating factor, we show for the first time that reduced Hox gene expression is specific to loss of MLL-ENL and is not a consequence of differentiation. Our data also suggest that the Hox cofactor Meis-2 can substitute for Meis-1 function. Thus, MLL-ENL is required to initiate and maintain immortalization of myeloid progenitors and may contribute to leukemogenesis by aberrantly sustaining the expression of a "Hox code" consisting of Hoxa4 to Hoxa11.

Original languageEnglish
Pages (from-to)9245-9252
Number of pages8
JournalCancer Research
Volume65
Issue number20
DOIs
Publication statusPublished - 15 Oct 2005
Externally publishedYes

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