Tal-1 induces T cell acute lymphoblastic leukemia accelerated by casein kinase IIalpha.

Abstract

Ectopic activation of the TAL‐1 gene in T lymphocytes occurs in the majority of cases of human T cell acute lymphoblastic leukemia (T‐ALL), yet experiments to date have failed to demonstrate a direct transforming capability for tal‐1. The tal‐1 gene product is a serine phosphoprotein and basic helix‐loop‐helix (bHLH) transcription factor known to regulate embryonic hematopoiesis. We have established a transgenic mouse model in which tal‐1 mis‐expression in the thymus results in the development of clonal T cell lymphoblastic leukemia/lymphoma. Thus, overexpression of tal‐1 alone can be transforming, verifying its pathogenic role in human T‐ALL. In addition, leukemogenesis is accelerated dramatically by transgenic co‐expression of tal‐1 and the catalytic subunit of casein kinase IIalpha (CKIIalpha), a serine/threonine protein kinase known to modulate the activity of other bHLH transcription factors. Although tal‐1 is a substrate for CKII, the synergy of the tal‐1 and CKIIalpha transgenes appears to be indirect, perhaps mediated through the E protein heterodimeric partners of tal‐1. These studies prove that dysregulated tal‐1 is oncogenic, providing a direct molecular explanation for the malignancies associated with TAL‐1 activation in human T‐ALL.

The CD2-scl transgene alters the phenotype and frequency of T-lymphomas in N-ras transgenic or p53 deficient mice

“…These data provide further evidence that scl is oncogenic. Recently, two groups have shown that Tcell lymphomas can spontaneously occur in scl transgenic mice when transcription is driven by the lck promoter (Condorelli et al, 1996;Kelliher et al, 1996). However, the latency of tumours in the lck-scl transgenics was at least 6 months and the tumour onset was stochastic, implicating additional genetic events.…”

“…For example, the CD2-scl transgene accelerates lymphomagenesis in LMO-2 transgenic mice, presumably by increasing the number of scl-LMO-2 heterodimers (Larson et al, 1996). Also, lymphomagenesis in lckscl mice is enhanced by the co-expression of a case in kinase IIa transgene (Kelliher et al, 1996). It was suggested that this e ect may be due to phosphorylation of an scl binding partner, E2A.…”

“…Although there was evidence that scl could function as an oncogene in a v-abl transformed murine cell line , transgenic mice carrying scl coupled to the human T-lymphoid speci®c CD2 enhancer (CD2-scl) did not develop T-cell malignancies despite high levels of scl expression in their thymocytes (Robb et al, 1995b;Larson et al, 1996). Recently, a role for scl in leukemogenesis was con®rmed by two groups who showed that animals carrying an scl transgene driven by the proximal lck promoter develop thymic T-cell lymphomas (Condorelli et al, 1996;Kelliher et al, 1996). The discrepancies of these results may be due to di erent timing of expression.…”

p16Ink4a or p19Arf loss contributes to Tal1-induced leukemogenesis in mice

“…We and others have shown that misexpression of Tal1 in the thymus alters thymocyte development by interfering with the expression of E47/HEB target genes including Rag1/2, Pre-Ta, CD4, CD5, CD3 and the TCRabchains (Herblot et al, 2000;O'Neil et al, 2001O'Neil et al, , 2004. Although Tal1 induces leukemia in mice, it does so after a long latency revealing that additional genetic events are required (Condorelli et al, 1996;Kelliher et al, 1996). Analysis of the INK4A/ARF locus in human T-ALL patients has revealed frequent homozygous deletion of exon 2, the exon common to both p16 INK4A and p14 ARF genes (Hebert et al, 1994;Cayuela et al, 1995Cayuela et al, , 1996Drexler, 1998;Gardie et al, 1998;Ferrando et al, 2002).…”

p300 functions as a transcriptional coactivator for the TAL1/SCL oncoprotein

“…Direct evidence for this has come from studies in mice involving enforced expression of a TAL1 transgene targeted to the thymus Kelliher et al, 1996), although other genetic lesions in the malignant T-cell likely cooperate in this process (Rabbitts, 1998).…”