SCL, LMO1 and Notch1 reprogram thymocytes into self-renewing cells

Bastien Gerby, Cedric Tremblay, Mathieu Tremblay, Shanti Rojas-Sutterlin, Sabine Herblot, Josee Hebert, Guy Sauvageau, Sebastien Lemieux, Eric Lecuyer, Diogo F T Veiga, Hoang Trang

Research output: Contribution to journalArticleResearchpeer-review

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.
Original languageEnglish
Article numbere1004768
Number of pages19
JournalPLoS Genetics
Volume10
Issue number12
DOIs
Publication statusPublished - 2014

Cite this

Gerby, B., Tremblay, C., Tremblay, M., Rojas-Sutterlin, S., Herblot, S., Hebert, J., ... Trang, H. (2014). SCL, LMO1 and Notch1 reprogram thymocytes into self-renewing cells. PLoS Genetics, 10(12), [e1004768]. https://doi.org/10.1371/journal.pgen.1004768
Gerby, Bastien ; Tremblay, Cedric ; Tremblay, Mathieu ; Rojas-Sutterlin, Shanti ; Herblot, Sabine ; Hebert, Josee ; Sauvageau, Guy ; Lemieux, Sebastien ; Lecuyer, Eric ; Veiga, Diogo F T ; Trang, Hoang. / SCL, LMO1 and Notch1 reprogram thymocytes into self-renewing cells. In: PLoS Genetics. 2014 ; Vol. 10, No. 12.
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title = "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.",
author = "Bastien Gerby and Cedric Tremblay and Mathieu Tremblay and Shanti Rojas-Sutterlin and Sabine Herblot and Josee Hebert and Guy Sauvageau and Sebastien Lemieux and Eric Lecuyer and Veiga, {Diogo F T} and Hoang Trang",
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Gerby, B, Tremblay, C, Tremblay, M, Rojas-Sutterlin, S, Herblot, S, Hebert, J, Sauvageau, G, Lemieux, S, Lecuyer, E, Veiga, DFT & Trang, H 2014, 'SCL, LMO1 and Notch1 reprogram thymocytes into self-renewing cells' PLoS Genetics, vol. 10, no. 12, e1004768. https://doi.org/10.1371/journal.pgen.1004768

SCL, LMO1 and Notch1 reprogram thymocytes into self-renewing cells. / Gerby, Bastien; Tremblay, Cedric; Tremblay, Mathieu; Rojas-Sutterlin, Shanti; Herblot, Sabine; Hebert, Josee; Sauvageau, Guy; Lemieux, Sebastien; Lecuyer, Eric; Veiga, Diogo F T; Trang, Hoang.

In: PLoS Genetics, Vol. 10, No. 12, e1004768, 2014.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - SCL, LMO1 and Notch1 reprogram thymocytes into self-renewing cells

AU - Gerby, Bastien

AU - Tremblay, Cedric

AU - Tremblay, Mathieu

AU - Rojas-Sutterlin, Shanti

AU - Herblot, Sabine

AU - Hebert, Josee

AU - Sauvageau, Guy

AU - Lemieux, Sebastien

AU - Lecuyer, Eric

AU - Veiga, Diogo F T

AU - Trang, Hoang

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

UR - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270438/pdf/pgen.1004768.pdf

U2 - 10.1371/journal.pgen.1004768

DO - 10.1371/journal.pgen.1004768

M3 - Article

VL - 10

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 12

M1 - e1004768

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Gerby B, Tremblay C, Tremblay M, Rojas-Sutterlin S, Herblot S, Hebert J et al. SCL, LMO1 and Notch1 reprogram thymocytes into self-renewing cells. PLoS Genetics. 2014;10(12). e1004768. https://doi.org/10.1371/journal.pgen.1004768