Allogeneic hematopoietic cell transplantation (allo-HCT) remains to be the only curative treatment for myelofibrosis (MF) but is associated with significant toxicity; it is therefore crucial to identify high-risk patients who might benefit from alternative therapies. In this issue of Blood, Hernández-Boluda et al. develop an improved machine-learning-based model and web-based application to predict high risk of allo-HCT for the treatment of MF.

Epstein-Barr virus (EBV) infects >90% of humans and is associated with both hematological and epithelial malignancies. Here, we analyzed 990 EBV genomes (319 newly sequenced and 671 from public databases) from patients with various diseases to comprehensively characterize genomic variations, including single nucleotide variations (SNVs) and structural variations (SVs). Although most SNVs were a result of conservative evolution and reflected the geographical origins of the viral genomes, we identified several convergent SNV hot spots within the central homology domain of EBNA3B, the transactivation domain of EBNA2, and the second transmembrane domain of LMP1. These convergent SNVs seem to fine-tune viral protein functionality and immunogenicity. SVs, particularly large deletions, were frequently observed in chronic active EBV disease (28%), EBV-positive diffuse large B-cell lymphoma (48%), extranodal natural killer/T-cell lymphoma (41%), and Burkitt lymphoma (25%), but were less common in infectious mononucleosis (11%), posttransplant lymphoproliferative disorder (7%), and epithelial malignancies (5%). In hematological malignancies, deletions often targeted viral microRNA clusters, potentially promoting viral reactivation and lymphomagenesis. Nondeletion SVs, such as inversions, were also prevalent, with several inversions disrupting the C promoter to suppress latent gene expression, thereby maintaining viral dormancy. Furthermore, recurrent EBNA3B deletions suggested that this viral transcription factor functions as a tumor suppressor. EBNA3B knockout experiments in vitro revealed downregulation of human tumor suppressors, including PTEN and RB1, which could explain the enhanced lymphomagenesis observed in EBNA3B-deficient lymphoblastoid cell line xenografts. Our findings highlight both disease-specific and general contributions of EBV genomic alterations to human cancers, particularly in hematological malignancies.

Loss-of-function (LoF) mutations frequently found in human cancers are generally intractable by classical small molecule inhibitor approaches. Among them are mutations affecting Polycomb-group (PcG) epigenetic regulators, enhancer of zeste homolog 2 (EZH2) and Additional sex combs like 1 (ASXL1), frequently found in hematological malignancies of myeloid or lymphoid lineage, and their concurrent mutations associates with particularly poor prognosis. Although there is a clear need to develop novel and effective treatments for these patients, the lack of appropriate disease models and mechanistic insights have significantly hindered the progress. Here, we show that genetic inactivation of Asxl1 and Ezh2 in murine hematopoietic stem/progenitor cells results in highly penetrant hematological malignancies as observed in corresponding human diseases. These PcG proteins regulate both coding and noncoding genomes, leading to marked reactivation of transposable elements (TEs) and DNA damage responses in PcG LoF-mutated cells, which create a novel vulnerability for poly(ADP-ribose) polymerase (PARP) inhibitor (PARPi)-induced synthetic lethality. Using both mouse models and primary patient samples, we demonstrate that Asxl1/Ezh2-mutated cells are highly sensitive to PARPis that induce excessive DNA damage and significantly extend disease latency. Intriguingly, the observed PARPi sensitivity can be specifically overridden by reverse transcriptase inhibitors that interrupt target site-primed reverse transcription and life cycle of TEs. This mechanism is contrastingly different from the current concept of BRCAness associated PARPi-induced synthetic lethality, which largely rely on deficient homologous recombination, and is independent on reverse transcriptase inhibitors. Together, this study reveals a novel application and mechanism of PARPi-induced synthetic lethal targeting of blood cancers with reactivated TEs such as those carrying PcG epigenetic mutations.

Acquired somatic mutations are incorporated in the classification and prognosis of myelodysplastic syndromes/neoplasms (MDSs). However, the predictive role of molecular features in MDS needs to be elucidated, especially in the lower-risk subtypes (LR-MDS), where treatment has become heterogeneous and predictive biomarkers are lacking. In this study, we investigated genetic markers associated with erythropoiesis-stimulating agents (ESAs) response in LR-MDS. A European cohort of 535 patients with LR-MDS was analyzed using targeted next-generation sequencing (t-NGS) to calculate molecular prognostic scores (International Prognostic Scoring System, molecular [IPSS-M]). The integration of IPSS-M score among the 2 known variables, serum erythropoietin (sEPO) and transfusion dependence (TD), refined the capability to predict response (area under the curve [AUC], 0.71 vs 0.63, P = .0004). Based on these 3 variables, a molecular predictive score, which we named ESA-PSS-M (-0.05 × [sEPO U/L] -4.5 × [IPSS-M score] -5 × [TD (yes = 1; no = 0)]; specificity 76%; sensitivity 57%), was generated and validated in an external cohort (n = 223 patients with LR-MDS). Despite the impact of IPSS-M score, no single mutated gene was linked to ESA response; however, when we stratified cases by sex at birth, the X-linked STAG2 gene mutations were significantly associated with ESA resistance in males with LR-MDS (odds ratio, 0.13; P = .003). To our knowledge, this is the first study based on a large multicenter cohort of patients suggesting that the integration of IPSS-M score and sex-specific mutations can characterize ESA resistance and guide first-line (1L) therapeutic choices for anemic LR-MDS (ie, ESAs vs luspatercept).

Liver sinusoidal endothelial cells (LSECs) are essential for maintaining liver function by actively sensing nutrients and producing angiocrine factors. LSECs also regulate systemic iron metabolism by secreting bone morphogenetic proteins (BMPs), which are key modulators of systemic iron homeostasis. However, the mechanism by which LSECs sense iron to regulate iron metabolism remains unclear. Here, we identify that the endothelial transcriptional factor forkhead box protein O1 (Foxo1) and its upstream protein kinase, mechanistic target of rapamycin complex 2 (mTORC2), as critical iron sensors. In response to iron, Foxo1 undergoes acute and dynamic nuclear translocation to activate the transcription of Bmp2 and Bmp6, thereby stimulating the synthesis of iron-regulatory hormone hepcidin in adjacent hepatocytes. Foxo1 directly binds evolutionally conserved Foxo binding sites within the Bmp2 and Bmp6 promoters to mediate this response. Mechanistically, iron triggers the lysosomal degradation of the mTORC2-specific component rapamycin-insensitive companion of mTOR (Rictor), enhancing Foxo1 activation. Endothelial-specific Foxo1 deletion reduces the expressions of hepatic Bmp2/6 and hepcidin, leading to systemic iron overload, whereas endothelial Rictor deletion increases the expressions of hepatic Bmp2/6 and hepcidin, producing an iron-deficient phenotype. Moreover, endothelial-targeted lipid nanoparticles expressing endothelial-specific and constitutively active Foxo1 alleviate iron overload in a murine model of hereditary hemochromatosis. Collectively, our study establishes the endothelial mTORC2-Foxo1 axis as an iron-responsive regulator of Bmp2 and Bmp6 expression and identifies it as a promising target for iron-related disorders.