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.
Chromosomal translocations in T-cell acute leukemias can activate genes encoding putative transcription factors such as the LIM proteins RBTN1 and RBTN2 and the DNA-binding basic helix-loop-helix transcription factor TAL1 associated with T-cell acute lymphocytic 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.
Aberrant expression of transcription factor oncogenes such as HOX11, HOX11L2, TAL1/SCL, LYL1, LMO1, and LMO2 can be detected in lymphoblasts from up to 80% of patients with acute T-cell lymphoblastic leukemia (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.
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.
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.
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.
Here we find that retroviral overexpression of IL2RG in human CD34+ cells has no effect on T-cell development, whereas overexpression of the T-cell acute lymphoblastic leukaemia (T-ALL) oncogene LMO2 leads to severe abnormalities.
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.
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.
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.
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.
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.
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.
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].