MEIS2 Is an Adrenergic Core Regulatory Transcription Factor Involved in Early Initiation of TH-MYCN-Driven Neuroblastoma Formation.

Roughly half of all high-risk neuroblastoma patients present with MYCN amplification. The molecular consequences of MYCN overexpression in this aggressive pediatric tumor have been studied for decades, but thus far, our understanding of the early initiating steps of MYCN-driven tumor formation is still enigmatic. We performed a detailed transcriptome landscaping during murine TH-MYCN-driven neuroblastoma tumor formation at different time points. The neuroblastoma dependency factor MEIS2, together with ASCL1, was identified as a candidate tumor-initiating factor and shown to be a novel core regulatory circuit member in adrenergic neuroblastomas. Of further interest, we found a KEOPS complex member (gm6890), implicated in homologous double-strand break repair and telomere maintenance, to be strongly upregulated during tumor formation, as well as the checkpoint adaptor Claspin (CLSPN) and three chromosome 17q loci CBX2, GJC1 and LIMD2. Finally, cross-species master regulator analysis identified FOXM1, together with additional hubs controlling transcriptome profiles of MYCN-driven neuroblastoma. In conclusion, time-resolved transcriptome analysis of early hyperplastic lesions and full-blown MYCN-driven neuroblastomas yielded novel components implicated in both tumor initiation and maintenance, providing putative novel drug targets for MYCN-driven neuroblastoma

Targeting cytokine- and therapy-induced PIM1 activation in preclinical models of T-cell acute lymphoblastic leukemia and lymphoma

T-cell acute lymphoblastic leukemia and lymphoma (T-ALL/T-LBL) are aggressive hematological malignancies that are currently treated with high dose chemotherapy. Over the last years, the search towards novel and less toxic therapeutic strategies for T-ALL/T-LBL patients has largely focused on the identification of cell intrinsic properties of the tumor cell. However, non cell autonomous activation of specific oncogenic pathways might also offer opportunities that could be exploited at the therapeutic level. In line with this, we here show that endogenous IL7 can increase the expression of the oncogenic kinase PIM1 in CD127+ T-ALL/T-LBL, thereby rendering these tumor cells sensitive to in vivo PIM inhibition. In addition, using different CD127+ T-ALL/T-LBL xenograft models, we also reveal that residual tumor cells, which remain present after short-term in vivo chemotherapy, display consistent upregulation of PIM1 as compared to bulk non-treated tumor cells. Notably, this effect was transient as increased PIM1 levels were not observed in reestablished disease after abrogation of the initial chemotherapy. Furthermore, we uncover that this phenomenon is, at least in part, mediated by the ability of glucocorticoids to cause transcriptional upregulation of IL7RA in T-ALL/T-LBL PDX cells, ultimately resulting in non-cell autonomous PIM1 upregulation by endogenous IL7. Finally, we confirm in vivo that chemotherapy in combination with a pan-PIM inhibitor can improve leukemia survival in a PDX model of CD127+ T-ALL. Altogether, our work reveals that IL7 and glucocorticoids coordinately drive aberrant activation of PIM1 and suggests that IL7 responsive CD127+ T-ALL and T-LBL patients could benefit from PIM inhibition during induction chemotherapy

Paradoxical co-existing base metal sulphides in the mantle: The multi-event record preserved in Loch Roag peridotite xenoliths, North Atlantic Craton

The role of the subcontinental lithospheric mantle as a source of precious metals for mafic magmas is contentious and, given the chalcophile (and siderophile) character of metals such as the platinum-group elements (PGE), Se, Te, Re, Cu and Au, the mobility of these metals is intimately linked with that of sulphur. Hence the nature of the host phase(s), and their age and stability in the subcontinental lithospheric mantle may be of critical importance. We investigate the sulphide mineralogy and sulphide in situ trace element compositions in base metal sulphides (BMS) in a suite of spinel lherzolite mantle xenoliths from northwest Scotland (Loch Roag, Isle of Lewis). This area is situated on the margin of the North Atlantic Craton which has been overprinted by a Palaeoproterozoic orogenic belt, and occurs in a region which has undergone magmatic events from the Palaeoproterozoic to the Eocene. We identify two populations of co-existing BMS within a single spinel lherzolite xenolith (LR80) and which can also be recognised in the peridotite xenolith suite as a whole. Both populations consist of a mixture of Fe-Ni-Cu sulphide minerals, and we distinguished between these according to BMS texture, petrographic setting (i.e., location within the xenolith in terms of ‘interstitial’ or within feldspar-spinel symplectites, as demonstrated by X-ray Computed Microtomography) and in situ trace element composition. Group A BMS are coarse, metasomatic, have low concentrations of total PGE (< 40 ppm) and high (Re/Os)N (ranging 1 to 400). Group B BMS strictly occur within symplectites of spinel and feldspar, are finer-grained rounded droplets, with micron-scale PtS (cooperite), high overall total PGE concentrations (15–800 ppm) and low (Re/Os)N ranging 0.04 to 2. Group B BMS sometimes coexist with apatite, and both the Group B BMS and apatite can preserve rounded micron-scale Ca-carbonate inclusions indicative of sulphide-carbonate-phosphate immiscibility. This carbonate-phosphate metasomatic association appears to be important in forming PGE-rich sulphide liquids, although the precise mechanism for this remains obscure. As a consequence of their position within the symplectites, Group B BMS are particularly vulnerable to being incorporated in ascending mantle-derived magmas (either by melting or physical entrainment). Based on the cross-cutting relationships of the symplectites, it is possible to infer the relative ages of each metasomatic BMS population. We tally these with major tectono-magmatic events for the North Atlantic region by making comparisons to carbonatite events recorded in crustal and mantle rocks, and we suggest that the Pt-enrichment was associated with a pre-Carboniferous carbonatite episode. This method of mantle xenolith base metal sulphide documentation may ultimately permit the temporal and spatial mapping of the chalcophile metallogenic budget of the lithospheric mantle, providing a blueprint for assessing regional metallogenic potential. Abbreviations: NAC, North Atlantic Craton; GGF, Great Glen Fault; NAIP, North Atlantic Igneous Province; BPIP, British Palaeogene Igneous Province; SCLM, subcontinental lithospheric mantle; PGE, platinum-group elements; HSE, highly siderophile elements; BMS, base metal sulphid

Quantitative diagnostics of soft tissue through viscoelastic characterization using time-based instrumented palpation

AbstractAlthough palpation has been successfully employed for centuries to assess soft tissue quality, it is a subjective test, and is therefore qualitative and depends on the experience of the practitioner. To reproduce what the medical practitioner feels needs more than a simple quasi-static stiffness measurement. This paper assesses the capacity of dynamic mechanical palpation to measure the changes in viscoelastic properties that soft tissue can exhibit under certain pathological conditions. A diagnostic framework is proposed to measure elastic and viscous behaviors simultaneously using a reduced set of viscoelastic parameters, giving a reliable index for quantitative assessment of tissue quality. The approach is illustrated on prostate models reconstructed from prostate MRI scans. The examples show that the change in viscoelastic time constant between healthy and cancerous tissue is a key index for quantitative diagnostics using point probing. The method is not limited to any particular tissue or material and is therefore useful for tissue where defining a unique time constant is not trivial. The proposed framework of quantitative assessment could become a useful tool in clinical diagnostics for soft tissue

Targeting BET proteins improves the therapeutic efficacy of BCL-2 inhibition in T-cell acute lymphoblastic leukemia

Inhibition of anti-apoptotic BCL-2 has recently emerged as a promising new therapeutic strategy for the treatment of a variety of human cancers, including leukemia. Here, we used T-cell acute lymphoblastic leukemia as a model system to identify novel synergistic drug combinations with the BH3 mimetic venetoclax (ABT-199). In vitro drug screening in primary leukemia specimens that were derived from patients with high risk of relapse or relapse and cell lines revealed synergistic activity between venetoclax and the BET bromodomain inhibitor JQ1. Notably, this drug synergism was confirmed in vivo using T-ALL cell line and patient-derived xenograft models. Moreover, the therapeutic benefit of this drug combination might, at least in part, be mediated by an acute induction of the pro-apoptotic factor BCL2L11 and concomitant loss of BCL-2 upon BET bromodomain inhibition, ultimately resulting in an enhanced binding of BIM (encoded by BCL2L11) to BCL-2. Altogether, our work provides a rationale to develop a new type of targeted combination therapy for selected subgroups of high-risk leukemia patients.Leukemia accepted article preview online, 11 January 2017. doi:10.1038/leu.2017.10

Temporal effects of mechanical loading on deformation-induced damage in skeletal muscle tissue

Mechanical loading of soft tissues covering bony prominences can cause skeletal muscle damage, ultimately resulting in a severe pressure ulcer termed deep tissue injury. Recently, by means of an experimental-numerical approach, it was shown that local tissue deformations cause tissue damage once a deformation threshold is exceeded. In the present study, the effects of load exposure time and intermittent load relief on the development of deformation-induced muscle damage were investigated. The data showed that a 2 h loading period caused more damage than 10 min loading. Intermittent load reliefs of 2 min during a 2 h loading period had minimal effect on the evolution of skeletal muscle damage. In addition, a local deformation threshold for damage was found, which was similar for each of the loading regimes applied in this study. For short loading periods, these results imply that local tissue deformations determine whether muscle damage will develop and the exposure time influences the amount of tissue damage. Temporary load reliefs were inefficient in reducing deformation-induced damage, but may still influence the development of ischemia-induced damage during longer loading period

Characterization of the genome-wide TLX1 binding profile in T-cell acute lymphoblastic leukemia

The TLX1 transcription factor is critically involved in the multi-step pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) and often cooperates with NOTCH1 activation during malignant T-cell transformation. However, the exact molecular mechanism by which these T-cell specific oncogenes cooperate during transformation remains to be established. Here, we used chromatin immunoprecipitation followed by sequencing to establish the genome-wide binding pattern of TLX1 in human T-ALL. This integrative genomics approach showed that ectopic TLX1 expression drives repression of T cell-specific enhancers and mediates an unexpected transcriptional antagonism with NOTCH1 at critical target genes, including IL7R and NOTCH3. These phenomena coordinately trigger a TLX1-driven pre-leukemic phenotype in human thymic precursor cells, reminiscent of the thymus regression observed in murine TLX1 tumor models, and create a strong genetic pressure for acquiring activating NOTCH1 mutations as a prerequisite for full leukemic transformation. In conclusion, our results uncover a functional antagonism between cooperative oncogenes during the earliest phases of tumor development and provide novel insights in the multi-step pathogenesis of TLX1-driven human leukemia.status: publishe

RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with inferior outcome compared to B-cell ALL. Here, we showed that Runt-related transcription factor 2, RUNX2 was upregulated in high-risk T-ALL with KMT2A rearrangements (KMT2A-R) or an immature immunophenotype. In KMT2A-R cells, we identified RUNX2 as a direct target of the KMT2A chimeras, where it reciprocally bound the KMT2A promoter, establishing a regulatory feed-forward mechanism. Notably, RUNX2 was required for survival of immature and KMT2A-R T-ALL cells in vitro and in vivo. We reported direct transcriptional regulation of CXCR4 signaling by RUNX2, thereby promoting chemotaxis, adhesion and homing to medullary and extramedullary sites. RUNX2 enabled these energy-demanding processes by increasing metabolic activity in T-ALL cells through positive regulation of both glycolysis and oxidative phosphorylation. Concurrently, RUNX2 upregulation increased mitochondrial dynamics and biogenesis in T-ALL cells. Finally, as a proof of concept, we demonstrated that immature and KMT2A-R T-ALL cells were vulnerable to pharmacological targeting of the interaction between RUNX2 and its co-factor CBFβ. In conclusion, we showed that RUNX2 acts as a dependency factor in high-risk subtypes of human T-ALL through concomitant regulation of tumour metabolism and leukemic cell migration

Genetic characterization and therapeutic targeting of MYC-rearranged T cell acute lymphoblastic leukaemia

Gloria Milani ... Charles Mullighan ... et al