Furthermore, the position of the LMO2 breakpoints in T-ALL in the light of the occurrence of TCRD-LMO2 translocations in normal thymocytes points to a critical role for the exact breakpoint location in determining LMO2 activation levels and the consequent pressure for T-ALL development.
Moreover, Foxp3 could interact with LMO2 and affect the expression level of TAL1, which was in accordance with the findings in T-cell acute lymphoblastic leukemia.
Gene expression studies indicate activation of a subset of these genes-HOX11, TAL1, LYL1, LMO1, and LMO2-in a much larger fraction of T-ALL cases than those harboring activating chromosomal translocations.
Hematopoietic transcription factor LIM domain only 2 (LMO2), a member of the TAL1 transcriptional complex, plays an essential role during early hematopoiesis and is frequently activated in T-cell acute lymphoblastic leukemia (T-ALL) patients.
One patient developed acute T cell acute lymphoblastic leukemia because of up-regulated expression of the proto-oncogene LMO-2 from insertional mutagenesis, but maintained a polyclonal T cell repertoire through chemotherapy and entered remission.
Accumulating evidence suggests that LMO1 and LMO2 act as oncogenic proteins in T-cell acute lymphoblastic leukemia, whereas LMO4 has recently been implicated in the genesis of breast cancer.
These T cell leukemias are clonally aneuploid, can be transplanted into irradiated recipient fish, and express the zebrafish orthologues of the human T-ALL oncogenes tal1/scl and lmo2, thus providing an animal model for the most prevalent molecular subgroup of human T-ALL.
We investigated the prognostic effect of the expression levels of eight oncogenic transcription factors--TLX1 (HOX11), TLX3 (HOX11L2), TAL1, TAL2, LYL1, OLIG2 (BHLHB1), LMO1, and LMO2--in 52 adults with T-cell acute lymphoblastic leukaemia.
The gene encoding LIM-only 2 (LMO2), an oncogenic transcription factor, is frequently activated in T cell acute lymphoblastic leukemia (T-ALL), but how LMO2 transforms primary hematopoietic cells to induce T-ALL remains an open question.McCormack et al. now show that, in mice, Lmo2 confers self-renewal potential on normally nonrenewing thymocyte progenitor cells, and this property is maintained over four serial transplantations when the cells are transplanted into irradiated mice that lack thymocytes.
In T-lymphocytes, aberrant LMO2 expression beyond those stages leads to T-cell acute lymphoblastic leukemia, while in B cells LMO2 is also expressed in germinal center lymphocytes and diffuse large B-cell lymphomas, where it predicts better clinical outcome.
Finally, we demonstrate that FOXP3 binds LMO2 in vitro, resulting in decreased interaction between LMO2 and TAL1, providing a molecular mechanism for FOXP3-mediated transcriptional modulation in T-ALL.
Thymic expression of the Tal1 and Lmo2 oncogenes in mice results in rapid development of T-ALL; and similar to T-ALL patients, more than half the leukemic mice develop spontaneous mutations in Notch1.
To account for the sharp contrast in rhom-2 expression seen in these T-ALLs, a model is proposed with a negative regulatory element in the T-ALLbcr locus that is disrupted in some of the cases leading to overexpression of rhom-2.
BACKGROUND The human LMO2 gene was first cloned from an acute T lymphocytic leukemia patient; it is primarily expressed in hematopoietic and vascular endothelial systems, and functions as a pivotal transcriptional regulator during embryonic hematopoiesis and angiogenesis.
Furthermore, we debate whether the integration near the LMO2 locus is sufficient to result in T-ALL-like proliferations or whether the gamma-retroviral viral expression of the therapeutic IL2RG gene contributes to leukemogenesis.
Seven patients developed acute leukemia [one acute myeloid leukemia (AML), four T cell acute lymphoblastic leukemia (T-ALL), and two primary T-ALL with secondary AML associated with a dominant clone with vector integration at the LMO2 (six T-ALL), MDS1 (two AML), or MN1 (one AML) locus].
Thus, the LMO2-LYL1 interaction is a promising therapeutic target for inhibiting self-renewing cancer stem cells in T-ALL, including poor-prognosis ETP-ALL cases.
This review describes three examples of this general paradigm of leukaemogenesis: RUNX1 abnormalities in acute leukaemias, GATA1 mutations in the leukaemias of Down syndrome, and SCL and LMO2 ectopic expression in T cell acute lymphoblastic leukaemia.
Subsequent studies on its role in tumours and in normal settings have highlighted LMO2 as an archetypical chromosomal translocation oncogene, activated by association with antigen receptor gene loci and a paradigm for translocation gene activation in T-ALL.