Abstract
The Lim Domain Only 2 (LMO2) leukaemia oncogene encodes an LIM domain transcriptional cofactor required for early haematopoiesis. During embryogenesis, LMO2 is also expressed in developing tail and limb buds, an expression pattern we now show to be recapitulated in transgenic mice by an enhancer in LMO2 intron 4. Limb bud expression depended on a cluster of HOX binding sites, while posterior tail expression required the HOX sites and two E-boxes. Given the importance of both LMO2 and HOX genes in acute leukaemias, we further demonstrated that the regulatory hierarchy of HOX control of LMO2 is activated in leukaemia mouse models as well as in patient samples. Moreover, Lmo2 knock-down impaired the growth of leukaemic cells, and high LMO2 expression at diagnosis correlated with poor survival in cytogenetically normal AML patients. Taken together, these results establish a regulatory hierarchy of HOX control of LMO2 in normal development, which can be resurrected during leukaemia development. Redeployment of embryonic regulatory hierarchies in an aberrant context is likely to be relevant in human pathologies beyond the specific example of ectopic activation of LMO2.
Highlights
The Lim Domain Only 2 (LMO2) gene encodes a transcriptional cofactor that forms multiprotein complexes with other transcription factors, such as Ldb[1], Scl/Tal[1], E2A and Gata1/Gata[21] and is widely expressed within the haematopoietic system with the exception of T cells
A conserved enhancer in LMO2 intron 4 is active during early limb and tail bud development Our previous analysis of the LMO2 locus identified a conserved region located 1 kb downstream of the LMO2 ATG, which directed expression to endothelial but not to blood cells when tested in transgenic mice in combination with the LMO2 proximal promoter.[8]
Following on from our discovery of a regulatory hierarchy between homeodomain factors and Lmo[2] during early embryonic development, we investigated whether evidence for a similar link could be detected in T-cell acute lymphoblastic leukaemia (T-ALL) patients
Summary
The Lim Domain Only 2 (LMO2) gene encodes a transcriptional cofactor that forms multiprotein complexes with other transcription factors, such as Ldb[1], Scl/Tal[1], E2A and Gata1/Gata[21] and is widely expressed within the haematopoietic system with the exception of T cells. Was originally identified through its involvement in recurrent chromosomal translocations.[3,4] Importantly, transgenic mouse models confirmed that ectopic expression of LMO2 in T cells constitutes an initiating leukaemogenic lesion.[5] Three distinct promoters and eight enhancer elements dispersed over 100 kb have been identified in the regulation of the LMO2 gene.[6,7,8,9,10] By contrast, the regulatory pathways that direct abnormal expression in T-ALL patients without LMO2 translocations are much less well understood
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