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| Leukaemia: A TALE of one Meis
The three-amino-acid loop extension (TALE) homeodomain protein MEIS1 induces and maintains mixed lineage leukemia (MLL) cancers by forming a DNA-binding transcriptional complex that promotes MLL oncogenic transformation. Fusion proteins including the mixed lineage leukaemia (MLL) histone methyltransferase induce several types of leukaemia by transforming myeloid progenitors into leukaemia stem cells (LSCs), partially through deregulation of Hox genes. However, deregulation of Hox genes alone is not sufficient to recapitulate MLL-rearranged leukaemias. Members of the three-amino-acid loop extension (TALE) class of homeodomain proteins, including the Meis and Pbx families, might also have a role in MLL leukaemias, as they enhance the DNA binding of Hox transcription factors and have been implicated in leukaemogenesis. Michael Cleary and colleagues now demonstrate that TALE homeodomain proteins, in particular MEIS1, have a crucial role in inducing and maintaining MLL leukaemias.
The authors first expressed 12 different MLL fusion proteins in primary mouse myeloid progenitor cells and found that Meis1 expression levels correlated with the latencies observed for leukaemias harbouring the various MLL fusion oncogenes. That is, higher Meis1 expression was observed in cells expressing MLL oncogenes that induce leukaemias with a shorter latency. In addition, transformation assays using fetal liver (FL) cells derived from Meis1-/- mice showed that these cells could not be transformed by MLL oncogenes, but transformation could be rescued by the expression of exogenous Meis1. Furthermore, expression of Meis1 short hairpin RNAs or a dominant-negative MEIS1 in wild-type FL cells expressing MLL fusions impaired clonogenic capacity. These data indicate that MEIS1 is involved in both the initiation and maintenance of MLL-mediated transformation. Does MEIS1 influence leukaemo-genesis in vivo? Myeloid progenitors expressing an MLL fusion oncogene and either Meis1 (MLL/Meis1) or an empty vector (MLL/v) were transplanted in equal numbers of colony-forming cells (CFCs) into syngeneic mice. The authors found that both cohorts of mice developed similar leukaemias, but leukaemias in mice transplanted with MLL/Meis1 cells had much shorter latencies. This correlated with reduced differentiation and increased proliferation, which seemed to be due to perturbation of the BMI1–INK4a axis. Furthermore, the numbers of CFCs in the spleens of leukaemic mice (which have the properties of LSCs) were sevenfold higher for MLL/Meis1 leukaemias than for MLL/v leukaemias. Thus, Meis1 serves a rate-limiting role in MLL leukaemogenesis. How does MEIS1 mediate MLL transformation? The authors carried out a structure–function analysis using various mutants of Meis1 and found that those incapable of interacting with Pbx TALE proteins were unable to rescue MLL transformation of Meis1-/- FL cells. Pbx2 and Pbx3 comprise 90% of total Pbx family expression in MLL-transformed myeloid progenitors. Loss of either Pbx2 or Pbx3 alone was not sufficient to block MLL transformation, but loss of both significantly reduced transformation. These data support the idea that MEIS1 forms a DNA-binding transcriptional complex with Pbx proteins to promote MLL transformation. Interestingly, MLL fusion genes that are associated with higher levels of MEIS1 expression are more prevalent in human leukaemias, suggesting that MEIS1 is also crucial for initiation and maintenance of these leukaemias. Therefore, investigation of TALE proteins, specifically MEIS1, as a therapeutic target is warranted. Sarah Seton-Rogers References
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