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Genetic data indicate that abrogation of Notch-Rbpj or Wnt-β-catenin pathways results in the loss of the intestinal stem cells (ISCs). However, whether the effect of Notch is direct or due to the aberrant differentiation of the transit-amplifying cells into post-mitotic goblet cells is unknown. To address this issue, we have generated composite tamoxifen-inducible intestine-specific genetic mouse models and analyzed the expression of intestinal differentiation markers. Importantly, we found that activation of β-catenin partially rescues the differentiation phenotype of Rbpj deletion mutants, but not the loss of the ISC compartment. Moreover, we identified Bmi1, which is expressed in the ISC and progenitor compartments, as a gene that is co-regulated by Notch and β-catenin. Loss of Bmi1 resulted in reduced proliferation in the ISC compartment accompanied by p16(INK4a) and p19(ARF) (splice variants of Cdkn2a) accumulation, and increased differentiation to the post-mitotic goblet cell lineage that partially mimics Notch loss-of-function defects. Finally, we provide evidence that Bmi1 contributes to ISC self-renewal. ; This work has been supported by the Instituto de Salud Carlos III [PI10/01128], Ministerio de Ciencia e Innovación [ACI2009-0918], Agència de Gestió d'Ajuts Universitaris i de Recerca-Convocatòria Estratègica-2010-0006 and Red Temática de Investigación Cooperativa en Cáncer [RD06/0020/0098, RD12/0036/0054]. The Mar Institute of Medical Research (IMIM) Foundation financed V.R., and she is a recipient of a European Molecular Biology Organization (EMBO) short-term fellowship [ASTF 20-2010]. E.L.-A. is funded by 'Fundación la Caixa' (2010) and the Department of Education, Universities and Research of the Basque Government [BFI-2011]. L.L.E. is an investigator of the Spanish National Health System (SNS) [CES08/006]

Background: Adult T cell acute lymphoblastic leukemia (T-ALL) is a rare disease that affects less than 10 individuals in one million. It has been less studied than its cognate pediatric malignancy, which is more prevalent. A higher percentage of the adult patients relapse, compared to children. It is thus essential to study the mechanisms of relapse of adult T-ALL cases. Results: We profile whole-genome somatic mutations of 19 primary T-ALLs from adult patients and the corresponding relapse malignancies and analyze their evolution upon treatment in comparison with 238 pediatric and young adult ALL cases. We compare the mutational processes and driver mutations active in primary and relapse adult T-ALLs with those of pediatric patients. A precise estimation of clock-like mutations in leukemic cells shows that the emergence of the relapse clone occurs several months before the diagnosis of the primary T-ALL. Specifically, through the doubling time of the leukemic population, we find that in at least 14 out of the 19 patients, the population of relapse leukemia present at the moment of diagnosis comprises more than one but fewer than 108 blasts. Using simulations, we show that in all patients the relapse appears to be driven by genetic mutations. Conclusions: The early appearance of a population of leukemic cells with genetic mechanisms of resistance across adult T-ALL cases constitutes a challenge for treatment. Improving early detection of the malignancy is thus key to prevent its relapse. ; The authors would like to thank the Asociación Española Contra el Cáncer (AECC) for financially supporting this project (GC16173697BIGA). N.L.-B. acknowledges funding from the European Research Council (consolidator grant 682398) and the ERDF/Spanish Ministry of Science, Innovation and Universities–Spanish State Research Agency/DamReMap Project (RTI2018-094095-B-I00). S. G work is supported by the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 754510. I. S is supported by FPI fellowship from Spanish Ministry of Economy and Competitiveness (project reference SAF2015-66084-R). V.G-H. is supported by the AECC (project reference GC16173697BIGA-9). IRB Barcelona is a recipient of a Severo Ochoa Centre of Excellence Award from the Spanish Ministry of Economy and Competitiveness (MINECO; Government of Spain) and is supported by CERCA (Generalitat de Catalunya).