Mutually exclusive oncogenic rearrangements may delineate specific T-cell acute lymphoblastic leukaemia (T-ALL) subgroups, and so far at least 4 molecular-cytogenetic subgroups have been identified, i.e. the TAL/LMO, the TLX1/HOX11, the TLX3/HOX11L2 and the HOXA subgroups.
HOX11, a divergent homeodomain-containing transcription factor, was isolated from the breakpoint of the nonrandom t(10;14)(q24;q11) chromosome translocation found in human T cell acute lymphoblastic leukemias.
Recent studies have revealed a rearrangement of a novel homeobox-containing gene called TCL-3 or HOX11 on 10q24 in T-cell acute lymphoblastic leukemia with the specific chromosome translocation t(10;14)(q24;q11), and thus the significance of 10q24 aberrations in leukemogenesis is indicated.
Molecular cloning of the t(10;14)(q24;q11) recurrent breakpoint of T cell acute lymphoblastic leukemia has demonstrated a transcript for the candidate gene TCL3.
Molecular analysis of the t(10;14) chromosomal translocation found in pediatric patients with T-cell acute lymphoblastic leukemia has led to the identification of the HOX-11 (TCL-3) protooncogene.
Here we show that PBX and Meis homeoproteins cooperatively bind the PBX-responsive sequence in vitro with the oncoprotein encoded by the non-clustered homeobox gene HOX11 activated by the t(10;14)(q24;q11) chromosomal translocation in T-cell acute lymphoblastic leukemia (T-ALL).
The t(10;14) chromosomal translocation of T-cell acute lymphoblastic leukemia joins the T-cell receptor delta gene to a region upstream of a diverged homeobox-containing gene called HOX11.
Here we describe the identification of another ABL1 fusion, EML1-ABL1, in a T-ALL patient with a cryptic t(9;14)(q34;q32) associated with deletion of CDKN2A (p16) and expression of TLX1 (HOX11).
Importantly, the disruption of the mitotic checkpoint in TLX1-induced tumors may be linked not only to the acquisition of secondary genetic alterations in T-ALL but also to increased sensitivity of these tumors to chemotherapy with drugs targeting the formation of the mitotic spindle.
The most common recurrent cytogenetic abnormalities in T-lymphoblastic leukemia (T-acute lymphoblastic leukemia [T-ALL]) involve T-cell receptor (TCR) loci and a variety of partner genes, including HOX11, HOX11L2, MYC, and TAL1.
Comparison of the tcl-3 cDNA and its 5' genomic sequences with DNA sequences from the t(10;14) translocation breakpoints showed that this gene is structurally altered in four patients with t(10;14)(q24;q11)T-ALL.
Loss or reduced levels of Ubr1 expression was associated with 5/14 spontaneous B-cell lymphomas in IgHmu-HOX11(Tg) mice and one of nine primary human T-ALLs.
TLX1- or TLX3-deregulated T-cell acute lymphoblastic leukemias (T-ALL; TLX1/3<sup>+</sup>) share an immature cortical phenotype and similar transcriptional signatures.
The relevance of these findings is discussed in the context of activating NOTCH1 mutations and the other genetic lesions implicated in the multistep transformation process of TLX1(+) T-ALL.
TAL1, LYL1, HOX11 and other transcription factors essential for normal hematopoiesis are often misexpressed in the thymus in T-cell acute lymphoblastic leukemia (T-ALL), leading to differentiation arrest and cell transformation.
Five different multistep molecular pathways have been identified that lead to T-ALL, involving activation of different T-ALL oncogenes: (1) HOX11, (2) HOX11L2, (3) TAL1 plus LMO1/2, (4) LYL1 plus LMO2, and (5) MLL-ENL.
The results suggest that the translocation of the TCR delta chain locus to a locus on 10q, which we have designated TCL3, results in deregulation of this putative oncogene, leading to acute T-cell leukemia.