Blood最新文献

We hypothesized that transcriptomic features among disease-driving hematopoietic stem and progenitor cells (HSPC) could improve the current paradigm for risk stratification in myelofibrosis (MF). Therefore, we performed bulk RNA-seq on blood from 358 MF patients split into training and test cohorts (ClinicalTrials.gov Identifier: NCT02760238). Single-cell (sc) RNA-seq data from Lin-CD34+ MF HSPCs were used to guide the development of a prognostic model trained on the bulk RNA-seq data. A NanoString assay was used to validate our final model in two independent cohorts of MF patients. We identified a 24-gene weighted-sum expression score (termed MPN24) that was prognostic of overall survival (OS). In two independent cohorts of 170 and 100 MF patients, MPN24-High scoring patients had worse 5-year OS compared to MPN24-Low scoring patients (25.5% vs 86.9%, HR = 9.81, P = 4.0e-11 and 23.5% vs 75.9%, HR = 6.40, P = 1.8e-7, respectively). MPN24-High was also associated with clinical, mutation and karyotypic features known to confer adverse risk in MF. The MPN24 score retained independent prognostic significance in multivariable analysis incorporating these covariates as well as existing risk stratification models including DIPSS, DIPSS Plus, MIPSS70, and MIPSS70 Plus v2.0, adding significant prognostic value to these risk stratification models (P = 1.6e-5, 4.0e-6, 1.5e-6, 5.4e-4, respectively). The MPN24 score was particularly useful in improving risk-stratification of DIPSS-Intermediate, and MIPSS70 Intermediate and High-risk patients. MPN24 is an HSPC-derived gene expression score that is associated with overall survival independent of clinical and genomic prognostic variables and improves risk stratification in MF.

A single, universally utilized tumor classification system is critical to ensure precision in patient care, clinical trial enrollment, and advancing therapy. Since the publication of the 3rd edition of the World Health Organization (WHO) classification in 2001, the hematology and hematopathology community had benefited from a single, widely accepted classification system. However, in 2022 two separate classifications of hematologic and lymphoid neoplasms emerged: the 5th edition of the WHO Classification of Hematolymphoid Tumours and the International Consensus Classification. This has created confusion and has resulted in a global call to action to return to a single classification system. In 2024, leaders of the Society of Hematopathology (SH) and European Association for Haematopathology (EA4HP) together with the leadership of WHO Classification of Tumours developed a plan to bridge the division and unite around the next edition of the WHO classification of hematologic and lymphoid tumours (WHO6). This plan entails convening a Classification Advancement Meeting (CAM), planned by SH and EA4HP with broad participation by pathologists, clinicians, and geneticists, to discuss and debate updates and changes to the existing classifications. Published conclusions of the CAM meeting will be available for independent consideration by the editorial board of WHO6. We are convinced that engagement of the broad community and leveraging global expertise to unite around WHO6 will critically benefit patients, medicine, and science.

The hematopoietic system performs essential functions for living organisms through a wide array of cell types, including immune cells for host defense, erythrocytes for oxygen transport and megakaryocytes involved in vascular and tissue repair. The adoptive transfer of mature blood cells and the transplantation of hematopoietic stem cells (HSCs) have been extensively exploited in clinical settings, for the treatment of inherited blood disorders as well as blood malignancies. In addition, blood cells are also preferential targets in the context of gene therapy, where they provide revolutionary treatments not only for classical hematologic diseases but also for novel and unexpected indications, such as inherited metabolic disorders. However, clinical bottlenecks remain, including the limited availability of suitably matched donor cells, the need for high cell doses, and the complexity of personalized manufacturing.Given their proliferative ability and capacity to generate any human cell type, human pluripotent stem cells (hPSCs), encompassing both embryonic stem cells (ESCs) and induced PSCs (iPSCs), represent a novel, potentially unlimited, easy-to-engineer source of either patient-specific or allogeneic blood cells for "off-the-shelf" cell therapies. In parallel, hPSC-derived blood cells enable in vitro modeling of diverse hematologic diseases and the identification of novel therapeutic targets. Recent advances describing protocols for the de novo generation of HSCs are opening new and exciting avenues for a broad application of hPSC-derived blood cells in both basic research and clinical medicine.

Abstract: MLL rearrangements (MLLrs) are the most common cause of congenital and infant leukemias. MLLrs arise prior to birth and can transform fetal/neonatal progenitors with the help of only a few additional cooperating mutations. Despite the low threshold for transformation, infant leukemias are rare, and congenital leukemias, which arise before birth, are even less common. These observations raise the question of whether mechanisms exist to suppress leukemic transformation during fetal life, thereby protecting the developing fetus from malignancy during a period of rapid hematopoietic progenitor expansion. To test this possibility, we used a mouse model of temporally controlled MLL::ENL expression to show that fetal MLL::ENL exposure establishes a heritable, leukemia-resistant state within hematopoietic progenitors that persists after birth. When we induced MLL::ENL expression prior to birth and transplanted hematopoietic stem and progenitor cells, very few recipient mice developed acute myeloid leukemia (AML) despite robust engraftment. When we induced MLL::ENL expression shortly after birth, all recipient mice developed a highly penetrant AML. Fetal MLL::ENL expression imposed a negative selective pressure on hematopoietic progenitors before birth followed by loss of self-renewal gene expression and enhanced myeloid differentiation after birth that precluded transformation. These changes did not occur when MLL::ENL expression initiated shortly after birth. The fetal barrier to transformation was enforced by the histone methyltransferase MLL3, and it could be overcome by cooperating mutations, such as NrasG12D. Heritable fetal protection against leukemic transformation may contribute to the low incidence of congenital and infant leukemias in humans.