Abstract
Chronic lymphocytic leukemia (CLL) is a B-cell malignancy with a mature phenotype. In spite of its relatively indolent nature, no radical cure is as yet available. CLL is not associated with either a unique cytogenetic or a molecular defect, which might have been a potential therapeutic target. Instead, several factors are involved in disease development, such as environmental signals which interact with genetic abnormalities to promote survival, proliferation and an immune surveillance escape. Among these, PI3-Kinase signal pathway alterations are nowadays considered to be clearly important. The TCL1 gene, an AKT co-activator, is the cause of a mature T-cell leukemia, as well as being highly expressed in all B-CLL. A TCL1 transgenic mouse which reproduces leukemia with a distinct immunophenotype and similar to the course of the human B-CLL was developed several years ago and is widely used by many groups. This is a review of the CLL biology arising from work of many independent investigators who have used TCL1 transgenic mouse model focusing on pathogenetic, microenviroment and therapeutic targets.
Highlights
Can microenvironment contribution and tumor immune suppression be more studied through animal models than in human patients?
TCL1FL-tg T-cell leukemia-1 oncogene (TCL1)-tg cells transplanted into C57bl/6 (i.v.) TCL1 transgenic mouse (TCL1-tg) cells transplanted into B6/ C3H (i.p.) TCL1-tg cells transplanted into C57bl/6 (i.p.) TCL1-tg TCL1-tg crossed with ROR-Tg TCL1-tg crossed with Pkc null TCL1-tg TCL1-tg cells transplanted into SCID (i.v.) TCL1-tg
TCL1-tg TCL1-tg TCL1-tg crossed with Id4+/ À TCL1-tg TCL1-tg TCL1-tg cells transplanted into SCID (i.v.) TCL1-tg crossed with p53 null TCL1-tg mice TCL1FL-tg cells transplanted into FVB (i.p.) TCL1-tg crossed with dnRag1-Tg TCL1-tg
Summary
Can microenvironment contribution and tumor immune suppression be more studied through animal models than in human patients?. The TCL1 gene was discovered as the causative oncogene of T-prolymphocytic leukemia (T-PLL), where it is overexpressed in almost 100% of cases by a chromosomal translocation.[14] TCL1 is expressed in human seminomas,[15] and in CD4 +/CD56+ skin blastic tumors[16] and in other B-cell lymphomas.[17] TCL1 is a low-molecular weight protein and its first recognized function was the activation of phosphoinositide 3-kinase (PI3K) pathway, implicated in cell proliferation and survival (Figure 1), through direct binding with the AKT1/2 kinases.[18] TCL1 binds to several other proteins and among these interacting proteins, the most relevant in CLL are: the receptor tyrosine kinase-like orphan receptor-1 (ROR1),[19] the p300 transcription factor and the AP1 components FOS and JUN,[20] the NFkB inhibitor alpha (IkBα),[21] the XBP1 transcription factor[22] and the DNA methyltransferases (DNMTs)[23,24] (Figure 2). The overexpression of TCL1 in transgenic animal models recapitulates faithfully leukemia of T-cell or B-cell origin according to the promoter used: the overexpression of TCL1 in T cells under Lck-promoter, recapitulates human T-PLL30 and the overexpression of TCL1 in B cells under the VH-promoter-IgH-Eμ-enhancer (TCL1-tg), recapitulates
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