Abundant and equipotent founder cells establish and maintain acute lymphoblastic leukaemia

High frequencies of blasts in primary acute lymphoblastic leukaemia (ALL) samples have the potential to induce leukaemia and to engraft mice. However, it is unclear how individual ALL cells each contribute to drive leukaemic development in a bulk transplant and the extent to which these blasts vary functionally. We used cellular barcoding as a fate mapping tool to track primograft ALL blasts in vivo. Our results show that high numbers of ALL founder cells contribute at similar frequencies to leukaemic propagation over serial transplants, without any clear evidence of clonal succession. These founder cells also exhibit equal capacity to home and engraft to different organs, although stochastic processes may alter the composition in restrictive niches. Our findings enhance the stochastic stem cell model of ALL by demonstrating equal functional abilities of singular ALL blasts and show that successful treatment strategies must eradicate the entire leukaemic cell population

Glucocorticoids and selumetinib are highly synergistic in RAS pathway-mutated childhood acute lymphoblastic leukemia through upregulation of BIM

New drugs are needed for relapsed acute lymphoblastic leukemia and preclinical evaluation of the MEK inhibitor, selumetinib, has shown excellent activity in those with RAS pathway mutations. The proapoptotic protein, BIM is pivotal in the induction of cell death by both selumetinib and glucocorticoids, suggesting the potential for synergy. Thus, combination indices for dexamethasone and selumetinib were determined in RAS pathway mutated acute lymphoblastic leukemia primagraft cells in vitro and were indicative of strong synergism (CI <0.2; n=5). Associated pharmacodynamic assays were consistent with the hypothesis that the drug combination enhanced BIM upregulation over single drug alone. Dosing of dexamethasone and selumetinib singly, and in combination in mice engrafted with primary derived RAS pathway mutated leukemia cells, resulted in a marked reduction in spleen size which was significantly greater with the drug combination. Assessment of the central nervous system leukaemia burden showed a significant reduction in drug treated mice, with no detectable leukemia in those treated with the drug combination. These data suggest that a selumetinib-dexamethasone combination may be highly effective in RAS pathway mutated acute lymphoblastic leukemia and an international phase I/II clinical trial of dexamethasone and selumetinib (Seludex trial) is underway for children with multiple relapsed/refractory disease

MAPK-ERK is a central pathway in T-cell acute lymphoblastic leukemia that drives steroid resistance

(Patho-)physiological activation of the IL7-receptor (IL7R) signaling contributes to steroid resistance in pediatric T-cell acute lymphoblastic leukemia (T-ALL). Here, we show that activating IL7R pathway mutations and physiological IL7R signaling activate MAPK-ERK signaling, which provokes steroid resistance by phosphorylation of BIM. By mass spectrometry, we demonstrate that phosphorylated BIM is impaired in binding to BCL2, BCLXL and MCL1, shifting the apoptotic balance toward survival. Treatment with MEK inhibitors abolishes this inactivating phosphorylation of BIM and restores its interaction with anti-apoptotic BCL2-protein family members. Importantly, the MEK inhibitor selumetinib synergizes with steroids in both IL7-dependent and IL7-independent steroid resistant pediatric T-ALL PDX samples. Despite the anti-MAPK-ERK activity of ruxolitinib in IL7-induced signaling and JAK1 mutant cells, ruxolitinib only synergizes with steroid treatment in IL7-dependent steroid resistant PDX samples but not in IL7-independent steroid resistant PDX samples. Our study highlights the central role for MAPK-ERK signaling in steroid resistance in T-ALL patients, and demonstrates the broader application of MEK inhibitors over ruxolitinib to resensitize steroid-resistant T-ALL cells. These findings strongly support the enrollment of T-ALL patients in the current phase I/II SeluDex trial (NCT03705507) and contributes to the optimization and stratification of newly designed T-ALL treatment regimens

Seasonal drought prediction for semiarid northeast Brazil: what is the added value of a process-based hydrological model?

The semiarid northeast of Brazil is one of the most densely populated dryland regions in the world and recurrently affected by severe droughts. Thus, reliable seasonal forecasts of streamflow and reservoir storage are of high value for water managers. Such forecasts can be generated by applying either hydrological models representing underlying processes or statistical relationships exploiting correlations among meteorological and hydrological variables. This work evaluates and compares the performances of seasonal reservoir storage forecasts derived by a process-based hydrological model and a statistical approach. Driven by observations, both models achieve similar simulation accuracies. In a hindcast experiment, however, the accuracy of estimating regional reservoir storages was considerably lower using the process-based hydrological model, whereas the resolution and reliability of drought event predictions were similar by both approaches. Further investigations regarding the deficiencies of the process-based model revealed a significant influence of antecedent wetness conditions and a higher sensitivity of model prediction performance to rainfall forecast quality. Within the scope of this study, the statistical model proved to be the more straightforward approach for predictions of reservoir level and drought events at regionally and monthly aggregated scales. However, for forecasts at finer scales of space and time or for the investigation of underlying processes, the costly initialisation and application of a process-based model can be worthwhile. Furthermore, the application of innovative data products, such as remote sensing data, and operational model correction methods, like data assimilation, may allow for an enhanced exploitation of the advanced capabilities of process-based hydrological models.</p

Seasonal drought prediction for semiarid northeastern Brazil: verification of six hydro-meteorological forecast products

A set of seasonal drought forecast models was assessed and verified for the Jaguaribe River in semiarid northeastern Brazil. Meteorological seasonal forecasts were provided by the operational forecasting system used at FUNCEME (Ceará's research foundation for meteorology) and by the European Centre for Medium-Range Weather Forecasts (ECMWF). Three downscaling approaches (empirical quantile mapping, extended downscaling and weather pattern classification) were tested and combined with the models in hindcast mode for the period 1981 to 2014. The forecast issue time was January and the forecast period was January to June. Hydrological drought indices were obtained by fitting a multivariate linear regression to observations. In short, it was possible to obtain forecasts for (a) monthly precipitation, (b) meteorological drought indices, and (c) hydrological drought indices.The skill of the forecasting systems was evaluated with regard to root mean square error (RMSE), the Brier skill score (BSS) and the relative operating characteristic skill score (ROCSS). The tested forecasting products showed similar performance in the analyzed metrics. Forecasts of monthly precipitation had little or no skill considering RMSE and mostly no skill with BSS. A similar picture was seen when forecasting meteorological drought indices: low skill regarding RMSE and BSS and significant skill when discriminating hit rate and false alarm rate given by the ROCSS (forecasting drought events of, e.g., SPEI1 showed a ROCSS of around 0.5). Regarding the temporal variation of the forecast skill of the meteorological indices, it was greatest for April, when compared to the remaining months of the rainy season, while the skill of reservoir volume forecasts decreased with lead time.This work showed that a multi-model ensemble can forecast drought events of timescales relevant to water managers in northeastern Brazil with skill. But no or little skill could be found in the forecasts of monthly precipitation or drought indices of lower scales, like SPI1. Both this work and those here revisited showed that major steps forward are needed in forecasting the rainy season in northeastern Brazil.</p

A phase I/II trial of AT9283, a selective inhibitor of aurora kinase in children with relapsed or refractory acute leukemia: challenges to run early phase clinical trials for children with leukemia.

Aurora kinases regulate mitosis and are commonly overexpressed in leukemia. This phase I/IIa study of AT9283, a multikinase inhibitor, was designed to identify maximal tolerated doses, safety, pharmacokinetics, and pharmacodynamic activity in children with relapsed/refractory acute leukemia. The trial suffered from poor recruitment and terminated early, therefore failing to identify its primary endpoints. AT9283 caused tolerable toxicity, but failed to show clinical responses. Future trials should be based on robust preclinical data that provide an indication of which patients may benefit from the experimental agent, and recruitment should be improved through international collaborations and early combination with established treatment strategies

A phase I/II trial of AT9283, a selective inhibitor of aurora kinase in children with relapsed or refractory acute leukemia: challenges to run early phase clinical trials for children with leukemia

Aurora kinases regulate mitosis and are commonly overexpressed in leukemia. This phase I/IIa study of AT9283, a multikinase inhibitor, was designed to identify maximal tolerated doses, safety, pharmacokinetics, and pharmacodynamic activity in children with relapsed/refractory acute leukemia. The trial suffered from poor recruitment and terminated early, therefore failing to identify its primary endpoints. AT9283 caused tolerable toxicity, but failed to show clinical responses. Future trials should be based on robust preclinical data that provide an indication of which patients may benefit from the experimental agent, and recruitment should be improved through international collaborations and early combination with established treatment strategies

A novel potent Fas agonist for selective depletion of tumor cells in hematopoietic transplants

There remains a clear need for effective tumor cell purging in autologous stem cell transplantation (ASCT) where residual malignant cells within the autograft contribute to disease relapse. Here we propose the use of a novel Fas agonist with potent pro-apoptotic activity, termed MegaFasL, as an effective ex-vivo purging agent. MegaFasL selectively kills hematological cancer cells from lymphomas and leukemias and prevents tumor development at concentrations that do not reduce the functional capacity of human hematopoietic stem/progenitor cells both in in vitro and in in vivo transplantation models. These findings highlight the potential use of MegaFasL as an ex-vivo purging agent in ASCT

Invariant Distances

In this chapter we shall define the (invariant) distance we are going to use, and collect some of its main properties we shall need later on