Comprehensive analysis of mesenchymal cells reveals a dysregulated TGF-β/WNT/HOXB7 axis in patients with myelofibrosis.

Despite the advances in the understanding and treatment of myeloproliferative neoplasm (MPN), the disease remains incurable with the risk of evolution to acute myeloid leukemia or myelofibrosis (MF). Unfortunately, the evolution of the disease to MF remains poorly understood, impeding preventive and therapeutic options. Recent studies in solid tumor microenvironment and organ fibrosis have shed instrumental insights on their respective pathogenesis and drug resistance, yet such precise data are lacking in MPN.

Engaging European society at the forefront of cancer research and care: How discussions at the 5 Gago Conference on European Science policy led to the Heidelberg Manifesto.

European cancer research stakeholders met in October 2022 in Heidelberg, Germany, at the 5 Gago conference on European Cancer Policy, to discuss the current cancer research and cancer care policy landscape in Europe. Meeting participants highlighted gaps in the existing European programmes focusing on cancer research, including Europe's Beating Cancer Plan (EBCP), the Mission on Cancer (MoC), Understanding Cancer (UNCAN.eu), and the joint action CRANE, and put forward the next priorities, in the form of the Heidelberg Manifesto for cancer research.

Factors Affecting Citizen Trust and Public Engagement Relating to the Generation and Use of Real-World Evidence in Healthcare.

The potential for the use of real-world data (RWD) to generate real-world evidence (RWE) that can inform clinical decision-making and health policy is increasingly recognized, albeit with hesitancy in some circles. If used appropriately, the rapidly expanding wealth of health data could improve healthcare research, delivery of care, and patient outcomes. However, this depends on two key factors: (1) building structures that increase the confidence and willingness of European Union (EU) citizens to permit the collection and use of their data, and (2) development of EU health policy to support and shape data collection infrastructures, methodologies, transmission, and use.

BCL-2 Inhibitor ABT-737 Effectively Targets Leukemia-Initiating Cells with Differential Regulation of Relevant Genes Leading to Extended Survival in a NRAS/BCL-2 Mouse Model of High Risk-Myelodysplastic Syndrome.

During transformation, myelodysplastic syndromes (MDS) are characterized by reducing apoptosis of bone marrow (BM) precursors. Mouse models of high risk (HR)-MDS and acute myelogenous leukemia (AML) post-MDS using mutant NRAS and overexpression of human BCL-2, known to be poor prognostic indicators of the human diseases, were created. We have reported the efficacy of the BCL-2 inhibitor, ABT-737, on the AML post-MDS model; here, we report that this BCL-2 inhibitor also significantly extended survival of the HR-MDS mouse model, with reductions of BM blasts and lineage negative/Sca1+/KIT+ (LSK) cells.

PLZF Acetylation Levels Regulate NKT Cell Differentiation.

The transcription factor promyelocytic leukemia zinc finger (PLZF) is encoded by the BTB domain-containing 16 () gene. Its repressor function regulates specific transcriptional programs. During the development of invariant NKT cells, PLZF is expressed and directs their effector program, but the detailed mechanisms underlying PLZF regulation of multistage NKT cell developmental program are not well understood.

The Benzene Hematotoxic and Reactive Metabolite 1,4-Benzoquinone Impairs the Activity of the Histone Methyltransferase SET Domain Containing 2 (SETD2) and Causes Aberrant Histone H3 Lysine 36 Trimethylation (H3K36me3).

Human SETD2 is the unique histone methyltransferase that generates H3K36 trimethylation (H3K36me3), an epigenetic mark that plays a key role in normal hematopoiesis. Interestingly, recurrent inactivating mutations of SETD2 and aberrant H3K36me3 are increasingly reported to be involved in hematopoietic malignancies. Benzene (BZ) is a ubiquitous environmental pollutant and carcinogen that causes leukemia.

Etoposide, an anticancer drug involved in therapy-related secondary leukemia: Enzymes at play.

Etoposide is a semi-synthetic glycoside derivative of podophyllotoxin, also known as VP-16. It is a widely used anticancer medicine in clinics. Unfortunately, high doses or long-term etoposide treatment can induce therapy-related leukemia.

Human CREBBP acetyltransferase is impaired by etoposide quinone, an oxidative and leukemogenic metabolite of the anticancer drug etoposide through modification of redox-sensitive zinc-finger cysteine residues.

Etoposide is an extensively prescribed anticancer drug that, unfortunately, causes therapy-related leukemia. The mechanisms by which etoposide induces secondary hematopoietic malignancies are poorly documented. However, etoposide-related leukemogenesis is known to depend on oxidative metabolites of etoposide, notably etoposide quinone, that can react with protein cysteine residues such as in topoisomerases II.

Feasibility of high-throughput sequencing in clinical routine cancer care: lessons from the cancer pilot project of the France Genomic Medicine 2025 plan.

Background: Whole exome sequencing and RNA sequencing (WES/RNASeq) should now be implemented in the clinical practice in order to increase access to optimal care for cancer patients. Providing results to Tumour Boards in a relevant time frame-that is, compatible with the clinical pathway-is crucial. Assessing the feasibility of this implementation in the French care system is the primary objective of the Multipli study, as one of the four pilot projects of the national France Genomic Medicine 2025 (FGM 2025) plan.

Prophylactic and therapeutic antileukemic effects induced by the AAC-11-derived Peptide RT53.

Despite considerable progress, the treatment of acute leukemia continues to be a challenge for a significant majority of patients. Using a well-characterized preclinical mouse model of acute promyelocytic leukemia (APL), we evaluated here the antileukemic efficacy of RT53, an anticancer peptide with potential immunological properties. Our results indicate that RT53 possesses a direct antileukemic effect, even at a late stage.

Correction: Despite mutation acquisition in hematopoietic stem cells, JMML-propagating cells are not always restricted to this compartment.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Despite mutation acquisition in hematopoietic stem cells, JMML-propagating cells are not always restricted to this compartment.

Juvenile myelomonocytic leukemia (JMML) is a rare aggressive myelodysplastic/myeloproliferative neoplasm of early childhood, initiated by RAS-activating mutations. Genomic analyses have recently described JMML mutational landscape; however, the nature of JMML-propagating cells (JMML-PCs) and the clonal architecture of the disease remained until now elusive. Combining genomic (exome, RNA-seq), Colony forming assay and xenograft studies, we detect the presence of JMML-PCs that faithfully reproduce JMML features including the complex/nonlinear organization of dominant/minor clones, both at diagnosis and relapse.

Benzoquinone, a leukemogenic metabolite of benzene, catalytically inhibits the protein tyrosine phosphatase PTPN2 and alters STAT1 signaling.

Protein tyrosine phosphatase, nonreceptor type 2 (PTPN2) is mainly expressed in hematopoietic cells, where it negatively regulates growth factor and cytokine signaling. PTPN2 is an important regulator of hematopoiesis and immune/inflammatory responses, as evidenced by loss-of-function mutations of in leukemia and lymphoma and knockout mice studies. Benzene is an environmental chemical that causes hematological malignancies, and its hematotoxicity arises from its bioactivation in the bone marrow to electrophilic metabolites, notably 1,4-benzoquinone, a major hematotoxic benzene metabolite.

T-Cell Protein Tyrosine Phosphatase Is Irreversibly Inhibited by Etoposide-Quinone, a Reactive Metabolite of the Chemotherapy Drug Etoposide.

Etoposide is a widely prescribed anticancer drug that is, however, associated with an increased risk of secondary leukemia. Although the molecular basis underlying the development of these leukemias remains poorly understood, increasing evidence implicates the interaction of etoposide metabolites [i.e.

Arsenic Trioxide Enhances the NK Cell Cytotoxicity Against Acute Promyelocytic Leukemia While Simultaneously Inhibiting Its Bio-Genesis.

Natural killer cells (NK) contribute significantly to eradication of cancer cells, and there is increased interest in strategies to enhance it's efficacy. Therapeutic agents used in the treatment of cancer can impact the immune system in a quantitative and qualitative manner. In this study, we evaluated the impact of arsenic trioxide (ATO) used in the management of acute promyelocytic leukemia (APL) on NK cell reconstitution and function.