NOTCH1 pathway activation is an early hallmark of SCL T leukemogenesis

Abstract

The acquired activation of stem cell leukemia (SCL) during T lymphopoiesis is a common event in T-cell acute lymphoblastic leukemia (T-ALL). Here, we generated tamoxifen (TAM)-inducible transgenic mice (lck-ER T2 -SCL) to study the consequences of acquired SCL activation during T-cell development. Aberrant activation of SCL in thymocytes resulted in the accumulation of immature CD4 ؉ CD8 ؉ (double-positive, DP) cells by preventing normal surface expression of the T-cell receptor ␣␤ (TCR␣␤) complex. SCLinduced immature DP cells were further characterized by up-regulated NOTCH1 and generated noncycling polyclonal CD8 ؉ TCR␤ low cells. The prevalence of these cells was SCL dependent because TAM withdrawal resulted in their disappearance. Furthermore, we observed that SCL activation led to a dramatic upregulation of NOTCH1 target genes (Hes-1, Deltex1, and CD25) in thymocytes. Strikingly, NOTCH1 target gene up-regulation was already observed after short-term SCL induction, implying that enhanced NOTCH signaling is mediated by SCL and is not dependent on secondary genetic events. These data represent the basis for a novel pathway of SCL-induced leukemogenesis and provide a functional link between SCL and NOTCH1 during this process. ( IntroductionThe basic helix-loop-helix (bHLH) transcription factor stem cell leukemia (SCL, also known as tal1 or tcl-5) is aberrantly expressed in a high proportion of pediatric and adult cases of T-cell acute lymphoblastic leukemia (T-ALL). 1,2 Normally, SCL is expressed in hematopoietic progenitor, erythroid and megakaryocytic cells, endothelium, and the central nervous system. 3,4 Within the thymus, regular SCL expression is restricted to the most primitive cellular compartment neither expressing CD4 nor CD8, referred to as double-negative (DN) cells. 5,6 During normal T-cell development, the in-frame rearrangement of the TCR␤ chain drives the differentiation of DN cells into double-positive (DP, CD4 ϩ CD8 ϩ ) cells via an intermediate CD8 immature single-positive (ISP) stage. This process, termed ␤-selection, is regulated by the pre-TCR, which comprises the CD3 complex in association with the rearranged TCR␤ chain and the invariant pre-TCR␣ chain. 7 Subsequently, the TCR␣ locus is recombined resulting in intermediate levels of the TCR␣␤ complex on the surface of DP cells. The majority of DP thymocytes die, either because they fail to express a TCR capable of interaction with self-peptide MHC complexes or because they bind too efficiently ("negative selection"). The appropriate, intermediate level of TCR signaling initiates effective maturation ("positive selection").Ectopic expression of SCL from the DN stage onward during T lymphopoiesis is thought to be one of the initiating events of T leukemogenesis. It was shown that the aberrant expression of SCL can be caused by chromosomal translocations and intrachromosomal deletions as well as by unknown mechanisms leading to the biallelic up-regulation of SCL. 3,5 In developing T cells, SCL has been shown to operate predominantly as a tr...

Notch signaling in acute lymphoblastic leukemia: any role for stromal microenvironment?

“…Mutated Notch1 probably cooperates with other oncogenic transcription factors, such as c-Myc, 6 E2A-PBX 45 and Ikaros, 46 but the aberrant Notch1 signaling itself is not sufficient for leukemic transformation. 47 Observations in animal models suggest that even nonmutational Notch1 activation contributes to leukemogenesis, 48 probably through the activation of c-Myc that is a direct downstream target of Notch1. 6 Actually, Notch1 pathway activation represents a common feature of T-ALL if compared with acute myeloid leukemia and B-ALL 49 : more than 50% of human T-ALL cases have gain-of-function mutations that involve the extracellular heterodimerization domain and/or the C-terminal PEST domain of Notch1.…”

NOTCH1 activation clinically antagonizes the unfavorable effect of PTEN inactivation in BFM-treated children with precursor T-cell acute lymphoblastic leukemia

“…Finally, the data presented here have unexpected and potentially profound implications for the development of NOTCH1 inhibitors for clinical use in T-ALL. Based on the role of NOTCH1 activity in T-ALL leukemogenesis 53,54 and the discovery of the common occurrence of activating NOTCH1 mutations in T-ALL, 44 the therapeutic inhibition of the NOTCH1 pathway has been a compelling perspective. 55 The data of this study suggest that some patients, and notably those with a combination of PTEN inactivation and NOTCH1 activation, may not benefit from the use of NOTCH1 inhibitors in multimodal treatment regimens, although the mechanism of the unexpected clinical interactions between NOTCH1 activation and PTEN inactivation remains to be explained.…”

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

“…tg mouse models of T-ALL (Lin et al 2006;O'Neil et al 2006;Gothert et al 2007). Members of the NOTCH family are evolutionary conserved proteins that control cell fate.…”