p16INK4A tumor suppressor gene expression and CD3ϵ deficiency but not pre-TCR deficiency inhibit TAL1-linked T-lineage leukemogenesis

Abstract

Inactivation of the CDKN2 genes that encode the p16 INK4A and p14 ARF proteins occurs in the majority of human T-cell acute lymphoblastic leukemias (T-ALLs). Ectopic expression of TAL1 and LMO1 genes is linked to the development of T-ALL in humans. In TAL1xLMO1 mice, leukemia develops in 100% of mice at 5 months. To identify the molecular events crucial to leukemic transformation, we produced several mouse models. We report here that expression of P16 INK4A in developing TAL1xLMO1 thymocytes blocks leukemogenesis in the majority of the mice, and the leukemias that eventually develop show P16 INK4A loss of expression. Events related to the T-cell receptor ␤ selection process are thought to be important for leukemic transformation. We show here that the absence of the pT␣ chain only slightly delays the appearance of TAL1xLMO1-induced T-ALL, which indicates a minor role of the pT␣ chain. We also show that the CD3⑀-mediated signal transduction pathway is essential for this transformation process, since the IntroductionT-cell acute lymphoblastic leukemias (T-ALLs) are considered to be due to the neoplastic transformation of thymocytes. [1][2][3][4] During normal ontogeny, the immature thymocytes proceed through 4 double-negative (DN1 to DN4) stages. At the DN3 stage, thymocytes rearrange the ␤ chain of the T-cell receptor (TCR) and assemble together with the pre-T alpha chain (pT␣) and then with the CD3 complex to constitute the pre-TCR. The proliferation of thymocytes, first driven by various interleukins and c-Kit, becomes driven by the pre-TCR/CD3. Pre-TCR signaling depends on the SRC-family kinase LCK, the SYKfamily kinase ZAP70, and the adaptor proteins SLP76 and LAT (reviewed in von Boehmer 5 ). Then, the phospholipase C-␥ and MAPK pathways are activated, which regulates some transcription factors required for the differentiation, proliferation, and survival of immature thymocytes. This activation leads to DN4 expansion followed by differentiation into double-positive (DP) CD4 ϩ CD8 ϩ thymocytes that do not proliferate. DP thymocytes are subjected to thymic selection and differentiate into CD4 or CD8 single-positive (SP) thymocytes that leave the thymus. 5 Although leukemic thymocytes present phenotypic similarities, it is not clear that they proceed through the same steps as normal thymocytes.Among the chromosomal abnormalities associated with T-ALL, the most frequent implicate the TAL1 and CDKN2 (INK4A and ARF) genes. The TAL1 gene (also known as SCL 6 ) encodes a transcription factor essential during erythroid lineage differentiation. 7,8 Chromosomal translocation or microdeletion next to the TAL1 locus were found in about 30% of the T-ALL cases leading to unscheduled TAL1 expression, and recent studies have noted TAL1 expression in about 49% of the pediatric T-ALL cases. 6,[9][10][11] In most cases, expression of the TAL1 gene was associated with expression of one of the LIM domain-only genes LMO1 or LMO2. 1,12,13 Furthermore, using a global gene expression analysis with the U133A microarray for 92 T-ALL c...

Modeling T-cell acute lymphoblastic leukemia induced by the SCL and LMO1 oncogenes

“…2A-4F) and the median survival increased by 234 d when compared with Cd3e +/+ littermates. Our results indicate a strong genetic interaction between the SCL-LMO1 oncogenes and Cd3e, but differ to some extent with the report by Fasseu et al (2007) showing a complete abrogation of SCL-LMO1-induced leukemogenesis in Cd3e À/À mice. This discrepancy is currently unresolved, but could be due to differences in genetic backgrounds.…”

“…The collaboration between CD3 and the SCL-LMO1 oncogenes is therefore antigen-independent and, hence, due to pre-TCR signaling. Our observations indicate that antigendependent TCR signaling has no discernible contribution to leukemogenesis when the pre-TCR is functional, although we do not exclude the possibility that TCR signaling could be a collaborating event when the pre-TCR is dysfunctional; for example, in the absence of pTa (Fasseu et al 2007). …”

“…In contrast, CD3 signaling is an important determinant, consistent with the report that all SCL-LMO1-induced T-ALL in SCID mice have an in-frame rearranged TCRb and express the pTa (Chervinsky et al 2001), suggesting a functional importance for the pre-TCR. Nonetheless, when the pre-TCR is inactive, as in pTa-deficient mice in which TCRa/b lymphocytes are still produced, albeit at reduced levels, it is possible that the TCRa/b or TCRg/d may provide an alternative collaborative signal for the SCL-LMO1 oncogenes, as reported (Fasseu et al 2007).…”

“…Previous work indicates that pre-TCR or TCR signaling (Chervinsky et al 2001;Fasseu et al 2007) accelerates SCLdependent leukemias in transgenic mouse models, and that SCL + T-ALL constitutes a poor prognostic group in childhood leukemias (Ferrando et al 2002), associated with elevated expression of genes of the TCR pathway. The relative importance of the pre-TCR or the TCR, however, remains debatable.…”

“…In the latter, the precise contribution of the pre-TCR to the leukemogenic process remains unknown. Finally, the importance of the pre-TCR was reported as minor in SCL-LMO1-dependent leukemias (Fasseu et al 2007), although SCL expression in childhood T-ALL is invariably associated with high TCR expression (Ferrando et al 2002). Furthermore, SCL-dependent leukemias in mice harbor in-frame TCRb rearrangements (Chervinsky et al 2001).…”