Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of the BCR::ABL1 fusion gene, which drives leukemogenesis through aberrant tyrosine kinase activity. While first- and second-generation tyrosine kinase inhibitors (TKIs) have transformed the management of CML, treatment failure due to resistance or intolerance—especially in patients with the T315I mutation—remains a critical concern. Asciminib, a first-in-class STAMP inhibitor targeting the myristoyl pocket of ABL1, offers a novel therapeutic approach distinct from ATP-competitive TKIs. This systematic review summarizes current evidence on the efficacy and safety of Asciminib in adults with CML who have failed at least two prior TKIs. Data from eight clinical trials involving 1,093 patients revealed that Asciminib demonstrated superior major molecular response rates compared to Bosutinib and Ponatinib in patients without the T315I mutation, along with a favorable safety profile marked by fewer grade ≥3 adverse events and treatment discontinuations. However, its efficacy in T315I-mutant CML remains inconclusive and warrants further investigation. The unique mechanism of Asciminib and its tolerability profile support its clinical utility as a third-line agent in CML, with potential future applications in combination therapies and treatment-free remission strategies.

The Magdalenian site of Courbet cave in the Aveyron valley is renowned for a significant contribution to the nineteenth century debate about human antiquity and an outstanding set of engraved and sculpted artworks. The typological content of the assemblage nevertheless remained poorly known, making it difficult to assess the place of Courbet cave within Magdalenian settlements of south-western France. This paper presents a review of over 1 300 pieces of osseous industry recovered during the main excavation led by the Vicomte de Lastic in 1863-64 and now curated at the British Museum. The assemblage composition corroborates the attribution of most of the collection to an Upper Magdalenian characterised by the prevalence of double bevel base points primarily decorated on the lateral faces, numerous barbed implements, and half -round rods decorated with a new variety of engravings. An earlier component includes single bevel base points and typical artworks documented in Middle Magdalenian layers at other sites. Locally, the osseous assemblage from Courbet cave bears a strong resemblance to that from Fontal & egrave;s and there is abundant evidence of contacts beyond the Aveyron valley. While some representations are indicative of close connections to the Pyrenean and North Aquitaine areas, the actual movement of some objects over long distances is confirmed by the unexpected identification of two artefacts made of whale bone imported from the Atlantic coast. This finding clearly shows the Magdalenian inhabitants of the Aveyron valley were part of wider networks.

Supplementary tables S1-S5 and supplementary figures S1-S5

KMT2A -rearranged (KMT2A-R) is an aggressive and chemo-refractory acute leukemia which mostly affects children. Transcriptomics-based characterization and chemical interrogation identified kinases as key drivers of survival and drug resistance in KMT2A -R leukemia. In contrast, the contribution and regulation of phosphatases is unknown. In this study we uncover the essential role and underlying mechanisms of SET, the endogenous inhibitor of Ser/Thr phosphatase PP2A, in KMT2A -R-leukemia. Investigation of SET expression in acute myeloid leukemia (AML) samples demonstrated that SET is overexpressed, and elevated expression of SET is correlated with poor prognosis and with the expression of MEIS and HOXA genes in AML patients. Silencing SET specifically abolished the clonogenic ability of KMT2A -R leukemic cells and the transcription of KMT2A targets genes HOXA9 and HOXA10 . Subsequent mechanistic investigations showed that SET interacts with both KMT2A wild type and fusion proteins, and it is recruited to the HOXA10 promoter. Pharmacological inhibition of SET by FTY720 disrupted SET-PP2A interaction leading to cell cycle arrest and increased sensitivity to chemotherapy in KMT2A -R-leukemic models. Phospho-proteomic analyses revealed that FTY720 reduced the activity of kinases regulated by PP2A, including ERK1, GSK3β, AURB and PLK1 and led to suppression of MYC, supporting the hypothesis of a feedback loop among PP2A, AURB, PLK1, MYC, and SET. Our findings illustrate that SET is a novel player in KMT2A -R leukemia and they provide evidence that SET antagonism could serve as a novel strategy to treat this aggressive leukemia.

Background: It would be clinically useful to prospectively identify the risk of disease progression in chronic myeloid leukaemia (CML). Overexpression of cancerous inhibitor of protein phosphatase 2A (PP2A) (CIP2A) protein is an adverse prognostic indicator in many cancers. Methods: We examined CIP2A protein levels in diagnostic samples from the SPIRIT2 trial in 172 unselected patients, of whom 90 received imatinib and 82 dasatinib as first-line treatment. Results: High CIP2A levels correlated with inferior progression-free survival (p = 0.04) and with worse freedom from progression (p = 0.03), and these effects were confined to dasatinib recipients. High CIP2A levels were associated with a six-fold higher five-year treatment failure rate than low CIP2A levels (41% vs. 7.5%; p = 0.0002), in both imatinib (45% vs. 11%; p = 0.02) and dasatinib recipients (36% vs. 4%; p = 0.007). Imatinib recipients with low CIP2A levels had a greater risk of treatment failure (p = 0.0008). CIP2A levels were independent of Sokal, Hasford, EUTOS (EUropean Treatment and Outcome Study), or EUTOS long-term survival scores (ELTS) or the presence of major route cytogenetic abnormalities. No association was seen between CIP2A levels and time to molecular response or the levels of the CIP2A-related proteins PP2A, SET, SET binding protein 1 (SETBP1), or AKT. Conclusions: These data confirm that high diagnostic CIP2A levels correlate with subsequent disease progression and treatment failure. CIP2A is a simple diagnostic biomarker that may be useful in planning treatment strategies.

Abstract Purpose: Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein that inhibits the tumor suppressor PP2A-B56α. However, CIP2A mRNA variants remain uncharacterized. Here, we report the discovery of a CIP2A splicing variant, novel CIP2A variant (NOCIVA). Experimental Design: Characterization of CIP2A variants was performed by both 3′ and 5′ rapid amplification of cDNA ends from cancer cells. The function of NOCIVA was assessed by structural and molecular biology approaches. Its clinical relevance was studied in an acute myeloid leukemia (AML) patient cohort and two independent chronic myeloid leukemia (CML) cohorts. Results: NOCIVA contains CIP2A exons 1 to 13 fused to 349 nucleotides from CIP2A intron 13. Intriguingly, the first 39 nucleotides of the NOCIVA-specific sequence are in the coding frame with exon 13 of CIP2A and code for a 13-amino acid peptide tail nonhomologous to any known human protein sequence. Therefore, NOCIVA translates to a unique human protein. NOCIVA retains the capacity to bind to B56α, but, whereas CIP2A is predominantly a cytoplasmic protein, NOCIVA translocates to the nucleus. Indicative of prevalent alternative splicing from CIP2A to NOCIVA in myeloid malignancies, AML and CML patient samples overexpress NOCIVA, but not CIP2A mRNA. In AML, a high NOCIVA/CIP2A mRNA expression ratio is a marker for adverse overall survival. In CML, high NOCIVA expression is associated with inferior event-free survival among imatinib-treated patients, but not among patients treated with dasatinib or nilotinib. Conclusions: We discovered a novel variant of the oncoprotein CIP2A and its clinical relevance in predicting tyrosine kinase inhibitor therapy resistance in myeloid leukemias.

Following the development of tyrosine kinase inhibitors (TKI), the survival of patients with chronic myeloid leukaemia (CML) drastically improved. With the introduction of these agents, CML is now considered a chronic disease for some patients. Taking into consideration the side effects, toxicity, and high cost, discontinuing TKI became a goal for patients with chronic phase CML. Patients who achieved deep molecular response (DMR) and discontinued TKI, remained in treatment-free remission (TFR). Currently, the data from the published literature demonstrate that 40–60% of patients achieve TFR, with relapses occurring within the first six months. In addition, almost all patients who relapsed regained a molecular response upon retreatment, indicating TKI discontinuation is safe. However, there is still a gap in understanding the mechanisms behind TFR, and whether there are prognostic factors that can predict the best candidates who qualify for TKI discontinuation with a view to keeping them in TFR. Furthermore, the information about a second TFR attempt and the role of gradual de-escalation of TKI before complete cessation is limited. This review highlights the factors predicting success or failure of TFR. In addition, it examines the feasibility of a second TFR attempt after the failure of the first one, and the current guidelines concerning TFR in clinical practice.

This paper presents a consideration on the spread of decorated weapon tips across Magdalenian societies. Based on a comprehensive review of the ten types of decorations identified on weapon tips from south-western France, the comparative analysis of their distribution shows their value to document both short and long distances relationships, depending on the types of decorated weapons. The distribution maps indeed highlight widespread cultural markers, such as the points and half-round rods with protuberances, coexisting with local and interregional types, the diffusion areas of which partly overlap. Some types with only limited distribution suggest local identities, especially in the cases of the points and half-round rods decorated with spirals and circles from the western Pyrenean Middle Magdalenian and the points and large bevelled rods with macrocephalic horses or fish-shaped patterns from the Upper Magdalenian of Dordogne. While the Pyrenean area retains the main sets for the decorated weapons from the Middle Magdalenian and therefore appears to have had a significant influence during this period, the decorated weapons from the Upper Magdalenian seem to originate from different areas. They tend to be essentially concentrated in different areas (Capra in frontal view along the Cantabrian coast, macrocephalic horses and fish-shaped patterns in Dordogne), supporting higher regional disparities. Furthermore, reduced evidence for links with the Cantabrian coast during the Upper Magdalenian also supports an evolution of the exchange networks in the course of the Magdalenian.

Cancerous inhibitor of PP2A (CIP2A) is a prevalent human oncoprotein that inhibits tumor suppressor PP2A-B56a. However, CIP2A mRNA and protein variants remain uncharacterized. Here, we report discovery of a CIP2A splicing variant NOCIVA (NOvel CIp2a VAriant). NOCIVA contains CIP2A exons 1-13 fused to a continuous stretch of 349 nucleotide from CIP2A intron 13. Intriguingly, the first 39 nucleotides of the NOCIVA specific sequence are in coding frame with exon 13 of CIP2A , and codes for a 13 amino acid peptide tail unhomologous to any known human protein sequence. Therefore, NOCIVA translates to a unique human protein. NOCIVA retains the capacity to bind to B56a, but whereas CIP2A is predominantly a cytoplasmic protein, NOCIVA translocates to nucleus. Indicative of prevalent alternative splicing from CIP2A to NOCIVA in myeloid malignancies, acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) patient samples overexpress NOCIVA , but not CIP2A mRNA. In AML, high NOCIVA mRNA expression is a marker for adverse overall survival. In CML, high NOCIVA expression associates with inferior event free survival among imatinib treated patients, but not among patients treated with dasatinib or nilotinib. Collectively, we describe discovery of a novel variant of oncoprotein CIP2A, and its clinical relevance in myeloid leukemias. Key Points Discovery and characterization of a first mRNA variant of one of the most prevalently deregulated human oncoproteins CIP2A Unlike CIP2A, NOCIVA mRNA is overexpressed in AML and CML patient samples and associates with poor clinical response in both myeloid cancers

The Magdalenian (20,500-13,000 cal. BP) is an important period for the cultural evolution of societies in the European Upper Palaeolithic. It is characterized by a great increase in settlements and products, probably reflecting demographic growth. Along with other material evidence, symbolic products (art and ornaments) clearly expand. In association with the multiplication of representations, some of them become highly normalized (included geometric signs) whereas others develop a great diversity of forms (such as human depictions). The density of sites and more-or-less normalized products make possible an original spatial interpretation, that is probably unprecedented for Palaeolithic societies. Beyond highlighting the diffusion of some concepts over long distances, these rich data allow a deeper analysis of exchange, influence, and non-influence connections. Consequently, the question arises of the identification of what can be called "territories" (spaces built and delimited by human occupations) or "symbolic territories". We define "symbolic territories" as spaces without visible material frontiers, symbolic through the weight of the ideas, the shared social norms and the installation of concepts by the societies in their close environment. We propose to examine this question through the prism of symbolic productions: body ornaments, portable art, rock art. Thousands of pieces of symbolic evidence assigned to the Magdalenian and a better stratigraphic definition for this period offer a favourable context for discussing the social implications of the results of several analyses: the distribution of themes in space, the presence of types of sign or figurative subjects contained in a narrow space, the identification of individual images and collective graphic norms. Comparing these approaches to series from the Middle and Upper Magdalenian, in which the evidence is the most abundant, will allow us to consider the nature of perceptible "territories". Then we will question the relationships between human groups through identity and mechanisms of otherness in Magdalenian societies. (c) 2017 Elsevier Ltd and INQUA. All rights reserved.

Taphonomic analyses at Palaeolithic sites contribute to explain the processes through which bone assemblages formed and accumulated, with a particular emphasis on the role played by humans. At most sites, the focus is generally on what agents were responsible for the formation of the assemblage. In this paper, in addition to discussing the zooarchaeological evidence and the taphonomy of La Lluera Cave (Asturias), we put forward a new analytical approach that aims to identify the most frequently used raw materials for the butchery of the animal carcasses found at the site. We analysed the cut-marks by means of three-dimensional reconstruction techniques, showing how they were made with both flint and quartzite. This interpretation is in line with the lithic assemblage found at the site, with both materials amply represented. Our results indicate that butchery practices were not significantly conditioned by, nor did they condition, raw material selection, in contrast with the patterns observed at other Palaeolithic sites.

A l'evidence, ces vingt dernieres annees ont vu en France, notamment, se developper en parallele deux nouvelles facons de traiter le Paleolithique superieur ancien qui ne sont pas antagonistes d'ailleurs. L'une consiste en une reprise des stratigraphies anciennes dans le Centre et le Sud-Ouest de la France plus specifi-quement et est associee a une meilleure redefinition des entites culturelles par l'analyse detaillee des differentes composantes des systemes techniques. L'autre s'efforce d'appliquer a cette periode la demarche palethnogra-phique, infeodee historiquement au Magdalenien du Bassin parisien. Il est vrai que peu de gisements autorisaient ce type d'approche, en raison d'une surface fouillee insuffisante ou d'un etat de conservation mediocre, mais meme lorsque les decouvertes s'y pretaient, le manque de temps et d'investissement freinait egalement toute velleite d'une etude approfondie des sites en question, qui aurait alors debouche sur une lecture palethnogra-phique des lieux et des artefacts. A l'issue d'un PCR mene entre 1999 et 2005, nous pouvions ainsi legitimement nous demander si nous etions capables de jouer les ethnologues du passe pour le Paleolithique superieur ancien dans le Bassin parisien. Les sites identifies dans le cadre de ce programme de recherche etaient certes nombreux mais representes surtout par des decouvertes de surface, ils ne garantissaient pas un niveau d'analyse digne de ce qui a pu se faire depuis plus de 50 ans a Pincevent ou a Etiolles par exemple (Bodu et al., 2013). Il aura fallu attendre la decouverte fortuite du gisement de plein-air d'Ormesson « les Bossats » (Seine-et-Marne, pres de Nemours) au debut des annees 2000 pour que cette question trouve une reponse positive. Concernant, au depart, presqu'exclusivement des vestiges lithiques et osseux attribues au Gravettien, les premieres fouilles menees en 2009 permirent d'identifier rapidement un second niveau d'occupation, d'attribution mousterienne. Les campagnes suivantes amenerent a la decouverte de cinq autres niveaux d'occupation paleolithiques, inegaux tant pour la surface couverte que pour l'etat de conservation : un second niveau mousterien resultant vraisemblablement de palimpsestes, un ensemble châtelperronien, un autre solutreen, un quatrieme badegoulien et enfin entre Châtelper-ronien et Gravettien, un foyer isole sans vestiges archeologiques associes. Cette stratigraphie paleolithique de plein-air dilatee est le temoignage d'une forte occupation du lieu pendant pres de 30 000 ans, ce qui s'explique notamment par la configuration particuliere de la vallee a cet endroit. A la diversite chronologique des occupations prehistoriques repond une diversite des comportements economiques et techniques au sein des differentes spheres d'activites mais egalement des habitudes spatiales differentes. A l'issue des huit premieres annees de fouille (2009-2016), le site d'Ormesson « les Bossats » permet ainsi de developper une approche detaillee des comportements techniques, economiques, spatiaux de groupes culturels distincts ayant vecu durant 30 000 ans dans un cadre geomorphologique et plus globalement naturel, relativement identique. Depassant le jeu de mot facile « palethno-graphie ou pâle ethnographie ? » a Ormesson « les Bossats », nous proposons ici quelques elements de reponse.

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an adverse biomarker across many malignancies. Using K562 cells engineered to have high or low CIP2A expression, we show that high CIP2A levels significantly bias cellular energy production towards oxidative phosphorylation (OXPHOS) rather than glycolysis. Mass spectrometric analysis of CIP2A interactors and isobaric tagging for relative and absolute protein quantitation (ITRAQ) experiments identified many associated proteins, several of which co-vary with CIP2A level. Many of these CIP2A associating and co-varying proteins are involved in energy metabolism including OXPHOS, or in 5' AMP-activated protein kinase (AMPK) signalling, and manipulating AMPK activity mimics the effects of low/high CIP2A on OXPHOS. These effects are dependent on the availability of nutrients, driven by metabolic changes caused by CIP2A. CIP2A level did not affect starvation-induced AMPK phosphorylation of Unc-51 autophagy activating kinase 1 (ULK-1) at Ser555, but autophagy activity correlated with an increase in AMPK activity, to suggest that some AMPK processes are uncoupled by CIP2A, likely via its inhibition of protein phosphatase 2A (PP2A). The data demonstrate that AMPK mediates this novel CIP2A effect on energy generation in malignant cells.

Perforated batons, usually made from a segment of antler and formed of a sub-cylindrical shaft and at least one perforation, have been documented across Europe from sites throughout the Upper Paleolithic and Mesolithic. The function of perforated batons is still debated. We present here three Magdalenian perforated batons from the site of Gough’s Cave (Somerset, UK); these are unique to Britain and represent an important northern example of this artifact type. Our technological analysis revealed that the Gough’s Cave perforated batons did not have a purely symbolic purpose, but were clearly used as tools as demonstrated by extensive use-wear on the perforations’ edges and ancient fractures across both the distal parts and the shafts. The reconstruction of the chaîne opératoire suggests that the engraving of the deep curved lines within the perforation of each baton was a functional re-adjustment following the significant distortion of the perforation by use. Additionally, oblique bands of incisions were engraved on two of the batons’ shafts possibly to provide grip on the smooth antler surface. Altogether, the modifications of the perforations and shafts of the three batons support the hypothesis that the Gough’s Cave batons were used in a task associated with ropes and subjected to considerable forces. Their extensive use may be due to the rarity of the raw material (reindeer antler) in the Cheddar Gorge area during the Magdalenian. Extensive usage aside, the Gough’s Cave batons fit typologically and share a number of features with other Magdalenian perforated batons. They can, therefore, add significant insight to the debate about the use of perforated batons.

LB100 sensitizes resistant chronic phase CML stem and progenitor cells to TKIs and spares healthy bone marrow cells.