Interleukin-18 produced by bone marrow- derived stromal cells supports T-cell acute leukaemia progression

International audienceDevelopment of novel therapies is critical for T-cell acute leukae-mia (T-ALL). Here, we investigated the effect of inhibiting the MAPK/MEK/ERK pathway on T-ALL cell growth. Unexpectedly, MEK inhibitors (MEKi) enhanced growth of 70% of human T-ALL cell samples cultured on stromal cells independently of NOTCH activa-tion and maintained their ability to propagate in vivo. Similar results were obtained when T-ALL cells were cultured with ERK1/ 2-knockdown stromal cells or with conditioned medium from MEKi-treated stromal cells. Microarray analysis identified interleu-kin 18 (IL-18) as transcriptionally up-regulated in MEKi-treated MS5 cells. Recombinant IL-18 promoted T-ALL growth in vitro, whereas the loss of function of IL-18 receptor in T-ALL blast cells decreased blast proliferation in vitro and in NSG mice. The NFKB pathway that is downstream to IL-18R was activated by IL-18 in blast cells. IL-18 circulating levels were increased in T-ALL-xeno-grafted mice and also in T-ALL patients in comparison with controls. This study uncovers a novel role of the pro-inflammatory cytokine IL-18 and outlines the microenvironment involvement in human T-ALL development

A biobank of pediatric patient-derived-xenograft models in cancer precision medicine trial MAPPYACTS for relapsed and refractory tumors

Pediatric patients with recurrent and refractory cancers are in most need for new treatments. This study developed patient-derived-xenograft (PDX) models within the European MAPPYACTS cancer precision medicine trial (NCT02613962). To date, 131 PDX models were established following heterotopical and/or orthotopical implantation in immunocompromised mice: 76 sarcomas, 25 other solid tumors, 12 central nervous system tumors, 15 acute leukemias, and 3 lymphomas. PDX establishment rate was 43%. Histology, whole exome and RNA sequencing revealed a high concordance with the primary patient's tumor profile, human leukocyte-antigen characteristics and specific metabolic pathway signatures. A detailed patient molecular characterization, including specific mutations prioritized in the clinical molecular tumor boards are provided. Ninety models were shared with the IMI2 ITCC Pediatric Preclinical Proof-of-concept Platform (IMI2 ITCC-P4) for further exploitation. This PDX biobank of unique recurrent childhood cancers provides an essential support for basic and translational research and treatments development in advanced pediatric malignancies

High-level IGF1R expression is required for leukemia-initiating cell activity in T-ALL and is supported by Notch signaling

Notch-driven expression of IGF1R promotes the growth, viability, and transplantability of T-ALL cells

La souris doublement immunodeficiente C57BL/6 nu/NU, bg/bg. Construction, caracterisation et utilisation pour l'etude de l'etiologie du syndrome autoimmun et lymphoproliferatif de la souris C57BL/6 lpr/lpr

SIGLEINIST TD 19990 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Comment un suppresseur de tumeur se prend au jeu de la prolifération leucémique chez l’homme

International audienc

Mise en évidence des cellules souches leucémiques dans les LAL-T humaines et étude de l’implication des voies NOTCH, TAL1 et ERK/MAPK dans la leucémogenèse T humaine

International audienc

The HOXB4 Homeoprotein Differentially Promotes Ex Vivo Expansion of Early Human Lymphoid Progenitors

International audienc

Assessment of Human Multi-Potent Hematopoietic Stem/Progenitor Cell Potential Using a Single <em>In Vitro</em> Screening System

<div><p>Hematopoietic stem cells are responsible for the generation of the entire blood system through life. This characteristic relies on their ability to self renew and on their multi-potentiality. Thus quantification of the number of hematopoietic stem cells in a given cell population requires to show both properties in the studied cell populations. Although xenografts models that support human hematopoietic stem cells have been described, such <em>in vivo</em> experimental systems remain restrictive for high throughput screening purposes for example. In this work we developed a conditional tetracycline inducible system controlling the expression of the human NOTCH ligand Delta-like 1 in the murine stromal MS5 cells. We cultured hematopoietic immature cells enriched in progenitor/stem cells in contact with MS5 cells that conditionally express Delta-like 1, in conditions designed to generate multipotential lineage differentiation. We show that upon induction or repression of DL1 expression during co-culture, human immature CD34⁺CD38^−/low(CD45RA⁻CD90⁺) cells can express their B, T, NK, granulo/monocytic and erythroid potentials in a single well, and at the single cell level. We also document the interference of low NOTCH activation with human B and myelo/erythroid lymphoid differentiation. This system represents a novel tool to precisely quantify human hematopoietic immature cells with both lymphoid and myeloid potentials.</p> </div

Characterization of MS5/DL1^ind cells lines.

<p>(A) Schematic representation of the TET/on lentiviral DL1 vector system. (B–D) Measure of DL1 expression in established MS5 cells. (B) Cell lines, previously transduced with 100 (/DL1^ind100), 500 (/DL1^ind500) or 1000 (/DL1^ind1000) ng P24 vectors, were cultured in presence (+) or absence (−) of 1 µg/ml of doxycyclin during 48 hours. Proteins were extracted and DL1 expression was analysed by western blot. (C) Follow up of DL1 induction. MS5/DL1^ind100–500 cells cultured with (+) or without (−) doxycyclin (1 µg/ml) were lysed at different times (in hours) after adding doxycyclin to the culture medium. (D) Follow up of DL1 drop down expression according to time after induction. DL1 expression was induced 24 hours before washing out medium (time 0 hour). At different time points, cells were harvested and protein extracted to follow up decrease of DL1 expression. (E) Surface expression of human DL1 in MS5 cell lines detected by flow cytometry. Shown are histograms of DL1 expression levels in presence of 1 µg/mL doxycycline (+ condition), after 48 hours of induction (- ->+condition) and 72 hours after washing out doxycycline from the medium (+ -> - condition). Arrows indicate positive and negative DL1 expression on cells. (F) Follow up on DL1 surface expression as a function of time after adding (+ doxycyclin) or washing out (-doxycyclin) doxycycline in the culture. Shown are % of DL1⁺ cells measured as in (E).</p