LIM-domain-only proteins in cancer

Key Points All members of the human LIM-domain-only (LMO) family of proteins, LMO1–4, are implicated in the onset or the progression of cancers. In particular, LMO1 and LMO2 are linked to the onset of T cell leukaemia; overexpression of LMO4 is a marker of poor prognosis in breast cancer; and LMO1 and LMO3 are associated with neuroblastoma. The overexpression of LMO2 in T cells is caused by chromosomal translocations (in which T cell receptor genes are inserted upstream of LMO2), chromosomal deletions, insertional mutagenesis during gene therapy trials for SCID-X1, and the upregulation of promoters though transcription factors such as FLI1, ERG and LMO2 itself. LMO2-induced T cell leukaemias have a long latency period. The overexpression of LMO2 results in the upregulation of haematopoietic stem cell genes and the downregulation of T cell differentiation genes, which causes developing thymocytes to stall at the DN3 stage and to undergo self-renewal. The self-renewing cells can accumulate additional mutations (such as activating mutations of NOTCH1) that trigger overt leukaemia. LMO2 seems to function primarily through forming transcription factor complexes with TAL1 or LYL1, GATA proteins, LDB1, and E12 or E47 to regulate gene expression. Other LMO proteins may function in the same way, but apart from LMO1 (which can take the place of LMO2 in haematopoietic transcriptional complexes) their protein partners are less well characterized. LMO4 seems to regulate progression through the cell cycle in breast cancer cell lines, and can act at several different stages of the cell cycle, probably either by affecting transcriptional programmes of proteins that directly control cell cycle progression, or through interaction with such proteins. The overexpression of LMO proteins has been identified in many different types of cancers. In some cases this overexpression can have a protective effect, in other cases the LMO proteins actively promote cancer, but in many other cases a causative or protective role has yet to be determined. In cancers in which LMO proteins are oncogenic, such as LMO2-induced T cell leukaemias, inhibitors of the LMO protein may be of therapeutic value. LIM-domain-only (LMO) proteins are a subset of the LIM-domain protein family and function primarily as transcriptional regulators. They are associated with various cancers, including T cell acute lymphoblastic leukaemia (T-ALL) that resulted from unintended activation of LMO2 by insertional mutage