Long-term in vitro maintenance of clonal abundance and leukaemia-initiating potential in acute lymphoblastic leukaemia

Lack of suitable in vitro culture conditions for primary acute lymphoblastic leukaemia (ALL) cells severely impairs their experimental accessibility and the testing of new drugs on cell material reflecting clonal heterogeneity in patients. We show that Nestin-positive human mesenchymal stem cells (MSCs) support expansion of a range of biologically and clinically distinct patient-derived ALL samples. Adherent ALL cells showed an increased accumulation in the S phase of the cell cycle and diminished apoptosis when compared with cells in the suspension fraction. Moreover, surface expression of adhesion molecules CD34, CDH2 and CD10 increased several fold. Approximately 20% of the ALL cells were in G0 phase of the cell cycle, suggesting that MSCs may support quiescent ALL cells. Cellular barcoding demonstrated long-term preservation of clonal abundance. Expansion of ALL cells for >3 months compromised neither feeder dependence nor cancer initiating ability as judged by their engraftment potential in immunocompromised mice. Finally, we demonstrate the suitability of this co-culture approach for the investigation of drug combinations with luciferase-expressing primograft ALL cells. Taken together, we have developed a preclinical platform with patient-derived material that will facilitate the development of clinically effective combination therapies for ALL

The Leukemia-Specific Fusion Gene ETV6/RUNX1 Perturbs Distinct Key Biological Functions Primarily by Gene Repression

-positive leukemic cell lines.-positive ALL samples underline the relevance of these pathways and molecular functions. We also validated six differentially expressed genes representing the categories “stem cell properties”, “B-cell differentiation”, “immune response”, “cell adhesion” and “DNA damage” with RT-qPCR. fusion gene interferes with key regulatory functions that shape the biology of this leukemia subtype. E/R may thus indeed constitute the essential driving force for the propagation and maintenance of the leukemic process irrespective of potential consequences of associated secondary changes. Finally, these findings may also provide a valuable source of potentially attractive therapeutic targets

Understanding the cancer stem cell

The last 15 years has seen an explosion of interest in the cancer stem cell (CSC). Although it was initially believed that only a rare population of stem cells are able to undergo self-renewing divisions and differentiate to form all populations within a malignancy, a recent work has shown that these cells may not be as rare as thought first, at least in some malignancies. Improved experimental models are beginning to uncover a less rigid structure to CSC biology, in which the concepts of functional plasticity and clonal evolution must be incorporated into the traditional models. Slowly the genetic programmes and biological processes underlying stem cell biology are being elucidated, opening the door to the development of drugs targeting the CSC. The aim of ongoing research to understand CSCs is to develop novel stem cell-directed treatments, which will reduce therapy resistance, relapse and the toxicity associated with current, non-selective agents

The mechanical implications of deep fluids in the rupture process of giant rocky landslides,

International audienceFluids are known to be a triggering and driving factor for landslides. Hydromechanical coupling has been proposed as possible explanation for landslide dynamics, including both slow, aseismic slip, as well as fast, seismic rupture. The widely accepted understanding is that rainfall, snowmelt and the seasonality of the groundwater recharge increases fluid pressures, which in turn reduces effective stress, and thus alters the strength of rocks and rupture surfaces, promoting sliding. So far, most interpretations focused on the effects of rainfall infiltration into landslides, and did not investigate in detail the role of groundwater table variations below the landslides on the rupture processes. However, such considerations are important, since observations of well-documented giant landslides showed that the moving volume extends hundreds of meters above the slope aquifer. Furthermore, although motions correlate well with seasonal infiltrations, no significant pore pressure increase has ever been measured within the landslide body, particularly in high-permeability rocky landslides. Indeed, motions occur in the near surface of the unsaturated slope, which is in general highly permeable (which allows high infiltration rates), perched, highly discontinuous, size-limited, and experiences low magnitude pore pressure build-up that is not high enough to significantly vary the effective stresses in the slope. Triggering of local instabilities by such perched low-pressurized zones may be possible only at the critical stress level of the rock, but do not explain the slow increase in the permanent background seasonal accelerations and decelerations that affect the entire landslide. Thus, clarifying the role of fluids, especially the effects of groundwater table variations within the deep aquifer on the unsaturated slope slow rupture is important for improved understanding of weak forcing mechanisms on landslides and risk assessment. The study of strain partitioning in two giant rocky landslides in France (La Clapière and Séchilienne, estimated volume of about 60 million cubic meters) provides a unique insight into the sensitivity of landslide motions to the changes in deep fluid pressures and surface frictional properties. Here we show with hydromechanical modeling that a significant part of the observed landslide motions and associated seismicity may be caused by poroelastic strain below the landslide, induced by groundwater table variations. In the unstable volume near the surface, calculated strain and rupture may be controlled by stress transfer and friction weakening above the phreatic zone and reproduce well high-motion zone characteristics measured by geodesy and seismology. The key model parameters are friction weakening and the position of groundwater level, which is sufficiently constrained by field data and seismic imaging to support the physical validity of the model. These results are of importance for the understanding of surface strain evolution under weak forcing and they demonstrated that the seasonal variation of deep fluids below the landslide is a major increasing factor of instability

Deep fluids can facilitate rupture of slow-moving giant landslides as a result of stress transfer and frictional weakening,

International audienceLandslides accommodate slow, aseismic slip and fast, seismic rupture, which are sensitive to fluid pressures and rock frictional properties. The study of strain partitioning in the Séchilienne landslide (France) provides a unique insight into this sensitivity. Here we show with hydromechanical modeling that a significant part of the observed landslide motions and associated seismicity may be caused by poroelastic strain below the landslide, induced by groundwater table variations. In the unstable volume near the surface, calculated strain and rupture may be controlled by stress transfer and friction weakening above the phreatic zone and reproduce well high-motion zone characteristics measured by geodesy and geophysics. The key model parameters are friction weakening and the position of groundwater level, which is sufficiently constrained by field data to support the physical validity of the model. These results are of importance for the understanding of surface strain evolution under weak forcing

The mechanical implications of deep fluids in the rupture process of giant rocky landslides,

International audienceFluids are known to be a triggering and driving factor for landslides. Hydromechanical coupling has been proposed as possible explanation for landslide dynamics, including both slow, aseismic slip, as well as fast, seismic rupture. The widely accepted understanding is that rainfall, snowmelt and the seasonality of the groundwater recharge increases fluid pressures, which in turn reduces effective stress, and thus alters the strength of rocks and rupture surfaces, promoting sliding. So far, most interpretations focused on the effects of rainfall infiltration into landslides, and did not investigate in detail the role of groundwater table variations below the landslides on the rupture processes. However, such considerations are important, since observations of well-documented giant landslides showed that the moving volume extends hundreds of meters above the slope aquifer. Furthermore, although motions correlate well with seasonal infiltrations, no significant pore pressure increase has ever been measured within the landslide body, particularly in high-permeability rocky landslides. Indeed, motions occur in the near surface of the unsaturated slope, which is in general highly permeable (which allows high infiltration rates), perched, highly discontinuous, size-limited, and experiences low magnitude pore pressure build-up that is not high enough to significantly vary the effective stresses in the slope. Triggering of local instabilities by such perched low-pressurized zones may be possible only at the critical stress level of the rock, but do not explain the slow increase in the permanent background seasonal accelerations and decelerations that affect the entire landslide. Thus, clarifying the role of fluids, especially the effects of groundwater table variations within the deep aquifer on the unsaturated slope slow rupture is important for improved understanding of weak forcing mechanisms on landslides and risk assessment. The study of strain partitioning in two giant rocky landslides in France (La Clapière and Séchilienne, estimated volume of about 60 million cubic meters) provides a unique insight into the sensitivity of landslide motions to the changes in deep fluid pressures and surface frictional properties. Here we show with hydromechanical modeling that a significant part of the observed landslide motions and associated seismicity may be caused by poroelastic strain below the landslide, induced by groundwater table variations. In the unstable volume near the surface, calculated strain and rupture may be controlled by stress transfer and friction weakening above the phreatic zone and reproduce well high-motion zone characteristics measured by geodesy and seismology. The key model parameters are friction weakening and the position of groundwater level, which is sufficiently constrained by field data and seismic imaging to support the physical validity of the model. These results are of importance for the understanding of surface strain evolution under weak forcing and they demonstrated that the seasonal variation of deep fluids below the landslide is a major increasing factor of instability

Characterization of karstic networks by automatic extraction of geometrical and topological parameters: comparison between observations and stochastic simulations

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