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.
Highlights
An important attribute of stem cell populations is the capacity to self-renew indefinitely both in normal development and during the process of cell transformation
While normal thymocytes did not engraft in transplanted hosts, SCLtgLMO1tg thymocytes afforded thymic reconstitution which was sustained through three serial transplantations (Fig. 1A–C)
A fraction of mice transplanted with DN1 and DN2 cells exhibited less than 1% engrafment and were ‘‘negative’’ by definition, this was different from the absence of engrafment from double positive (DP) cells
Summary
An important attribute of stem cell populations is the capacity to self-renew indefinitely both in normal development and during the process of cell transformation. Initially identified in acute myeloblastic leukemias [1], can self-renew indefinitely to propagate and maintain the disease [2]. This led to the experimental definition of leukemia initiating cell (LIC) characterized by their capacities to initiate the disease in transplanted host mice [1,3]. It was initially thought that the capacity for self-renewal of LICs, referred to as leukemic stem cells (LSCs), is conferred by the cell of origin of cancer, that is, primitive hematopoietic stem/progenitor cells (HSPCs), even though the leukemic phenotype is manifest in differentiating myeloblasts [3].
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