Genetic interaction between Kit and Scl

Lacombe, Julie; Krosl, Gorazd; Tremblay, Mathieu; Gerby, Bastien; Martin, Richard C.; Aplan, Peter D.; Lemieux, Sébastien; Hoang, Trang

doi:10.1182/blood-2011-01-331819

Cited by 24 publications

(21 citation statements)

References 53 publications

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“…Comparison of the transcriptomes of murine SCL-LMO1-induced T-ALLs and of their normal counterparts points to the regulation of apoptosis as a top gene ontology category among SCL targets (Supplemental Figure 10A). We observed that 2-ME2 induced apoptosis in vitro both in pre-LSCs and in T-ALL blasts from SCL tg LMO1 tg mice (Supplemental Figure 10B), consistent with an inhibition of SCL antiapoptotic function (49)(50)(51).…”

Section: -Me2 Kills Leukemic Blasts Without Affecting Viability Of Nsupporting

confidence: 71%

“…The percentages of cell viability are shown (right panel, n = 6, *P ≤ 0.05). IC 50 pre-LSCs ( Figure 2A). We found that MS5-DL4 lo cells sustained viability of SCL tg LMO1 tg pre-LSCs more efficiently than MS5 expressing higher DL4 levels ( Figure 2B).…”

Section: Resultsmentioning

confidence: 99%

“…SCL controls HSC self-renewal activity under stress (50,(66)(67)(68), and is redundant with Lyl1 during steady-state hematopoiesis (69). In contrast, SCL activation in thymocytes occurs in a context whereby other self-renewal genes are absent and therefore preLSCs are "addicted" to SCL.…”

Section: -Me2 Kills Leukemic Blasts Without Affecting Viability Of Nmentioning

confidence: 99%

“…VSV-G-producing cells transfected with the human DLL4 cDNA (MHS4426-98361330, GE Healthcare) were used for gene transduction in MS5 cells (48 hours) as described previously (50,66). Transduced MS5 cells were stained using rabbit anti-DLL4 (ab7280, Abcam), and 3 MS5 stromal cell lines were generated by cell sorting according to 3 levels of DL4 expression (low, medium, and high).…”

Section: Generation Of Ms5-dl4 Stromal Cell Linesmentioning

confidence: 99%

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High-throughput screening in niche-based assay identifies compounds to target preleukemic stem cells

Gerby¹,

Veiga²,

Krošl³

et al. 2016

Journal of Clinical Investigation

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Section: -Me2 Kills Leukemic Blasts Without Affecting Viability Of Nsupporting

confidence: 71%

Section: Resultsmentioning

confidence: 99%

Section: -Me2 Kills Leukemic Blasts Without Affecting Viability Of Nmentioning

confidence: 99%

Section: Generation Of Ms5-dl4 Stromal Cell Linesmentioning

confidence: 99%

See 2 more Smart Citations

High-throughput screening in niche-based assay identifies compounds to target preleukemic stem cells

Gerby¹,

Veiga²,

Krošl³

et al. 2016

Journal of Clinical Investigation

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“…tg mice was performed essentially as previously described [119]. Bone marrow cells were depleted of lineage positive cells through immunomagnetic bead cell separation (LIN -) and plated in suspension culture in IMDM with 15% FCS, 100 ng/mL murine Steel Factor (SF), 10 ng/mL human IL-6, 100 ng/ml human IL-11 and 5 ng/mL murine IL-3, at a concentration of 1610 6 cells/mL.…”

Section: Lmo1mentioning

confidence: 99%

SCL, LMO1 and NOTCH1 reprogram thymocytes into self-renewing cells

Gerby

2014

Experimental Hematology

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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 ligandindependent 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.

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