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Despite the recent evidence of the existence of myelodysplastic syndrome (MDS) stem cells in 5q-MDS patients, it is unclear whether haematopoietic stem cells (HSCs) could also be the initiating cells in other MDS subgroups. Here we demonstrate that SF3B1 mutation(s) in our cohort of MDS patients with ring sideroblasts can arise from CD34 + CD38 − CD45RA − CD90 + CD49f + HSCs and is an initiating event in disease pathogenesis. Xenotransplantation of SF3B1 mutant HSCs leads to persistent long-term engraftment restricted to myeloid lineage. Moreover, genetically diverse evolving subclones of mutant SF3B1 exist in mice, indicating a branching multi-clonal as well as ancestral evolutionary paradigm. Subclonal evolution in mice is also seen in the clinical evolution in patients. Sequential sample analysis shows clonal evolution and selection of the malignant driving clone leading to AML transformation. In conclusion, our data show SF3B1 mutations can propagate from HSCs to myeloid progeny, therefore providing a therapeutic target. Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders with diverse phenotypes and can derive from hematopietic stem cells after the acquisition of specific somatic aberrations. In this study, the authors show that MDS initiating cells in some cases of sideroblastic anemia with SF3B1 mutations, can arise from hematopoietic stem cells.

This paper presents a culture system that can be used as an in vitro surrogate for xenotransplantation and that has the potential to dramatically increase the throughput of the investigation of leukemia‐initiating cells, providing the means to identify and target the functionality of the different signaling pathways involved in the maintenance and resistance of leukemia‐initiating cells to improve acute myeloid leukemia treatments. Acute myeloid leukemia‐initiating cells (LICs) are responsible for the emergence of leukemia and relapse after chemotherapy. Despite their identification more than 15 years ago, our understanding of the mechanisms responsible for their self‐renewal activity and their chemoresistance remains poor. The slow progress in this area is partly due to the difficulty of studying these cells ex vivo. Indeed, current studies are reliant on xenotransplantation assays in immunodeficient mice. In this paper, we report that by modeling key elements of the bone marrow niche using different stromal feeder layers and hypoxic culture conditions, we can maintain LICs over at least 3 weeks and support their self‐renewal properties demonstrated through primary and secondary successful xenograft. We provide a proof of principle that this niche‐like culture system can be used to study LIC chemoresistance following in vitro cytarabine treatment similarly to the xenograft chemotherapy model. We found that although LICs are believed to be more chemoresistant than non‐LICs, functionally defined LICs are not enriched after cytarabine treatment, and heterogeneity in their resistance to treatment can be seen between patients and even within the same patient. We present a culture system that can be used as an in vitro surrogate for xenotransplantation and that has the potential to dramatically increase the throughput of the investigation of LICs. This would further provide the means by which to identify and target the functionality of the different signaling pathways involved in the maintenance and resistance of LICs to improve acute myeloid leukemia treatments.

Leukaemia immunotherapy represents a fascinating and promising field of translational research, particularly as an integrative approach of bone marrow transplantation. Adoptive immunotherapy by the use of donor-derived expanded leukaemia-specific T cells has showed some kind of clinical response, but the major advance is nowadays represented by gene manipulation of donor immune cells, so that they acquire strict specificity towards the tumour target and potent lytic activity, followed by significant proliferation, increased survival and possibly anti-tumour memory state. This is achieved by gene insertion of Chimeric T-cell Antigen Receptors (CARs), which are artificial molecules containing antibody-derived fragments (to bind the specific target), joined with potent signalling T-Cell Receptor (TCR)-derived domains that activate the manipulated cells. This review will discuss the main application of this approach particularly focusing on the paediatric setting, raising advantages and disadvantages and discussing relevant perspectives of use in the nearest future.

Adoptive transfer of specific cytotoxic T lymphocytes (CTL) and Cytokine Induced Killer Cells (CIK) following genetic engineering of T-cell receptor zeta hold promising perspective in immunotherapy. In the present work we focused on the mechanisms of anti-tumor action of effectors transduced with an anti-CD19 chimaeric receptor in the context of B-lineage acute lymphoblastic leukemia (B-ALL). Primary B-ALL blasts were efficiently killed by both z-CD19 CTL and z-CD19 CIK effectors. The use of death receptor mediated apoptosis of target cells was excluded since agonists molecules of Fas and TRAIL-receptors failed to induce cell death. Perforin/granzyme pathway was found to be the mechanism of chimaeric effectors mediated killing. Indeed, cytolytic effector molecules perforin as well as granzymes were highly expressed by CTL and CIK. CD19 specific stimulation of transduced effectors was associated with degranulation as attested by CD107 membrane expression and high IFN-γ and TNF-α release. Moreover inhibitors of the perforin-based cytotoxic pathway, Ca2+-chelating agent EGTA and Concanamycin A, almost completely abrogated B-ALL blast killing. In conclusion we show that the cytolysis response of z-CD19 chimaeric effectors is predominantly mediated via perforin/granzyme pathway and is independent of death receptors signaling in primary B-ALL.

Background Breast cancer screening recommendations are in flux. We reviewed the methods of detecting newly diagnosed breast neoplasms at our institution. Methods A retrospective review of patients stratified by age was performed to compare mammography with self- (SBE) and clinical (CBE) breast examination methods of cancer detection from 2005 to 2009. Results We identified 782 patients. Patients aged <50 years were more likely to present with palpable disease ( P  < 0.001). Overall, 75% of patients had a mammogram within 24 months. There was a higher incidence of Tis tumors and lower incidence of T1 tumors if patients had mammography performed within 12 months versus 13–24 months ( P  < 0.01); tumor size, hormonal status, and lymph node (LN) status were comparable between these two groups. Patients diagnosed by SBE/CBE who had mammography performed within 12 months versus 13–24 months did not differ statistically according to tumor characteristics. In the screened cohort (mammography within 24 months), the majority of patients (64%) were diagnosed by mammography. Cancers detected by SBE/CBE were larger tumors (2.4 vs. 1.3 cm), higher grade, more frequently ER- (29 vs. 16%), triple-negative (21 vs. 10%), and lymph node-positive (39 vs. 18%; all P  ≤ 0.01). There were no statistically significant differences in tumor size, T stage, or hormonal status in patients who had analog versus digital mammography. Conclusions Whereas the majority of patients had image-detected breast cancer, a significant number of image-screened patients presented with palpable disease, which were more aggressive cancers. Until imaging techniques are refined, SBE and CBE remain important for breast cancer diagnosis.