SCL, LMO1 and Notch1 Reprogram Thymocytes into Self-Renewing Cells

Abstract

The molecular determinants that render specific populations of normal cells susceptible to oncogenic reprogramming into self-renewing cancer stem cells are poorly understood. Here, we exploit T-cell acute lymphoblastic leukemia (T-ALL) as a model to define the critical initiating events in this disease. First, thymocytes that are reprogrammed by the SCL and LMO1 oncogenic transcription factors into self-renewing pre-leukemic stem cells (pre-LSCs) remain non-malignant, as evidenced by their capacities to generate functional T cells. Second, we provide strong genetic evidence that SCL directly interacts with LMO1 to activate the transcription of a self-renewal program coordinated by LYL1. Moreover, LYL1 can substitute for SCL to reprogram thymocytes in concert with LMO1. In contrast, inhibition of E2A was not sufficient to substitute for SCL, indicating that thymocyte reprogramming requires transcription activation by SCL-LMO1. Third, only a specific subset of normal thymic cells, known as DN3 thymocytes, is susceptible to reprogramming. This is because physiological NOTCH1 signals are highest in DN3 cells compared to other thymocyte subsets. Consistent with this, overexpression of a ligand-independent hyperactive NOTCH1 allele in all immature thymocytes is sufficient to sensitize them to SCL-LMO1, thereby increasing the pool of self-renewing cells. Surprisingly, hyperactive NOTCH1 cannot reprogram thymocytes on its own, despite the fact that NOTCH1 is activated by gain of function mutations in more than 55% of T-ALL cases. Rather, elevating NOTCH1 triggers a parallel pathway involving Hes1 and Myc that dramatically enhances the activity of SCL-LMO1 We conclude that the acquisition of self-renewal and the genesis of pre-LSCs from thymocytes with a finite lifespan represent a critical first event in T-ALL. Finally, LYL1 and LMO1 or LMO2 are co-expressed in most human T-ALL samples, except the cortical T subtype. We therefore anticipate that the self-renewal network described here may be relevant to a majority of human T-ALL.

Myogenic regulatory transcription factors regulate growth in rhabdomyosarcoma

“…For example, the TAL1/SCL bHLH transcription factor is required for hematopoietic stem cell specification and self-renewal during development. TAL1/SCL is overexpressed in 60% of T-cell acute lymphoblastic leukemia (T-ALL) (Ferrando et al, 2002) and can reprogram thymocytes into self-renewing, pre-leukemic cells (Gerby et al, 2014). This same paradigm has also been seen in brain tumors.…”

GATA3 Abundance Is a Critical Determinant of T Cell Receptor β Allelic Exclusion

“…Subsequently, one of 23 functional V␤ (variable) mouse gene segments is joined to the previously rearranged D␤J␤ recombinant at the DN3 stage (thereby generating VDJ recombinants) to generate a Tcrb gene encoding the ␤ chain of the pre-TCR complex (6,17,18). A similar VDJ rearrangement is also observed during B cell development at the immunoglobulin heavy chain gene (Igh) locus.…”

The Pluripotency Regulator PRDM14 Requires Hematopoietic Regulator CBFA2T3 to Initiate Leukemia in Mice

“…Scale bar, 100 mm ( ÃÃÃ , P < 0.0006; Ã , P < 0.05; ns, not significant). (34,35). Homozygous Cbfa2t3-mutant mice also have lower numbers of T cells, with primary perturbations in the DN1 populations (29).…”