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The human blood system is maintained through the differentiation and massive amplification of a limited number of long-lived haematopoietic stem cells (HSCs) 1 . Perturbations to this process underlie diverse diseases, but the clonal contributions to human haematopoiesis and how this changes with age remain incompletely understood. Although recent insights have emerged from barcoding studies in model systems 2 – 5 , simultaneous detection of cell states and phylogenies from natural barcodes in humans remains challenging. Here we introduce an improved, single-cell lineage-tracing system based on deep detection of naturally occurring mitochondrial DNA mutations with simultaneous readout of transcriptional states and chromatin accessibility. We use this system to define the clonal architecture of HSCs and map the physiological state and output of clones. We uncover functional heterogeneity in HSC clones, which is stable over months and manifests as both differences in total HSC output and biases towards the production of different mature cell types. We also find that the diversity of HSC clones decreases markedly with age, leading to an oligoclonal structure with multiple distinct clonal expansions. Our study thus provides a clonally resolved and cell-state-aware atlas of human haematopoiesis at single-cell resolution, showing an unappreciated functional diversity of human HSC clones and, more broadly, paving the way for refined studies of clonal dynamics across a range of tissues in human health and disease. An improved, single-cell lineage-tracing system, based on deep detection of naturally occurring mitochondrial DNA mutations with simultaneous readout of transcriptional states and chromatin accessibility, is used to define the clonal architecture of haematopoietic stem cells.

Monoclonal immunoglobulin deposition disease (MIDD) is a rare complication of plasma cell disorders, defined by linear Congo red-negative deposits of monoclonal light chain, heavy chain, or both along basement membranes. While renal involvement is prominent, treatment strategies, such as the impact of novel anti-myeloma agents, remain poorly defined. Here we retrospectively studied 49 patients with MIDD who received a median of 4.5 cycles of intravenous bortezomib plus dexamethasone. Of these, 25 received no additional treatment, 18 also received cyclophosphamide, while 6 also received thalidomide or lenalidomide. The hematological diagnoses identified 38 patients with monoclonal gammopathy of renal significance, 10 with symptomatic multiple myeloma, and 1 with Waldenstrom macroglobulinemia. The overall hematologic response rate, based on the difference between involved and uninvolved serum-free light chains (dFLCs), was 91%. After median follow-up of 54 months, 5 patients died and 10 had reached end-stage renal disease. Renal response was achieved in 26 patients, with a 35% increase in median eGFR and an 86% decrease in median 24-h proteinuria. Predictive factors were pre-treatment eGFR over 30ml/min per 1.73m2 and posttreatment dFLC under 40mg/l; the latter was the sole predictive factor of renal response by multivariable analysis. Thus, bortezomib-based therapy is a promising treatment strategy in MIDD, mainly when used early in the disease course. dFLC response is a favorable prognostic factor for renal survival.

Front-line treatment with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) is superior to standard ATRA and chemotherapy (CHT) in patients with low-/intermediate-risk acute promyelocytic leukemia (APL). However, for high-risk (HR) patients (defined as those with a white blood cell count ≥ 10×10⁹/L), the role of ATRA-ATO is subject to debate, and study data are scarce. The objective for the present real-world cohort study was to assess the outcomes in 135 HR APL patients treated with ATRA-CHT or ATRA-ATO during induction at 12 French hospitals between 2010 and 2021. Of the 135 patients, 50 (37%) received ATRA-ATO as induction therapy (though combination with cytoreductive treatment was usually necessary), and 85 received standard ATRA-CHT (\"CHT group\"). The complete response rates were 90% in the ATRA-ATO group and 76% in the CHT group (p = 0.052). The five-year overall survival (OS) rate was significantly higher in the ATRA-ATO group (89.86% [95% confidence interval: 81.81-98.70]) than in the CHT group (72.69% [63.30-83.47]; p = 0.035). The combination of ATRA and ATO was effective and safe in this large, real-world cohort of HR APL patients. The forthcoming results of the APOLLO trial (a direct comparison of ATRA-ATO with ATRA-CHT) might validate our present findings.

Front-line treatment with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) is superior to standard ATRA and chemotherapy (CHT) in patients with low-/intermediate-risk acute promyelocytic leukemia (APL). However, for high-risk (HR) patients (defined as those with a white blood cell count ≥ 10×10⁹/L), the role of ATRA-ATO is subject to debate, and study data are scarce. The objective for the present real-world cohort study was to assess the outcomes in 135 HR APL patients treated with ATRA-CHT or ATRA-ATO during induction at 12 French hospitals between 2010 and 2021. Of the 135 patients, 50 (37%) received ATRA-ATO as induction therapy (though combination with cytoreductive treatment was usually necessary), and 85 received standard ATRA-CHT (“CHT group”). The complete response rates were 90% in the ATRA-ATO group and 76% in the CHT group ( p  = 0.052). The five-year overall survival (OS) rate was significantly higher in the ATRA-ATO group (89.86% [95% confidence interval: 81.81–98.70]) than in the CHT group (72.69% [63.30–83.47]; p  = 0.035). The combination of ATRA and ATO was effective and safe in this large, real-world cohort of HR APL patients. The forthcoming results of the APOLLO trial (a direct comparison of ATRA-ATO with ATRA-CHT) might validate our present findings.

Among histone deacetylases, HDAC6 is unusual in its cytoplasmic localization. Its inhibition leads to hyperacetylation of non‐histone proteins, inhibiting cell cycle, proliferation and apoptosis. Ricolinostat (ACY‐1215) is a selective inhibitor of the histone deacetylase HDAC6 with proven efficacy in the treatment of malignant diseases, but anaemia is one of the most frequent side effects. We investigated here the underlying mechanisms of this erythroid toxicity. We first confirmed that HDAC6 was strongly expressed at both RNA and protein levels in CD34+‐cells‐derived erythroid progenitors. ACY‐1215 exposure on CD34+‐cells driven in vitro towards the erythroid lineage led to a decreased cell count, an increased apoptotic rate and a delayed erythroid differentiation with accumulation of weakly hemoglobinized immature erythroblasts. This was accompanied by drastic changes in the transcriptomic profile of primary cells as shown by RNAseq. In erythroid cells, ACY‐1215 and shRNA‐mediated HDAC6 knockdown inhibited the EPO‐dependent JAK2 phosphorylation. Using acetylome, we identified 14‐3‐3ζ, known to interact directly with the JAK2 negative regulator LNK, as a potential HDAC6 target in erythroid cells. We confirmed that 14‐3‐3ζ was hyperacetylated after ACY‐1215 exposure, which decreased the 14‐3‐3ζ/LNK interaction while increased LNK ability to interact with JAK2. Thus, in addition to its previously described role in the enucleation of mouse fetal liver erythroblasts, we identified here a new mechanism of HDAC6‐dependent control of erythropoiesis through 14‐3‐3ζ acetylation level, LNK availability and finally JAK2 activation in response to EPO, which is crucial downstream of EPO‐R activation for human erythroid cell survival, proliferation and differentiation.

Introduction Leukemogenesis is a complex process that interconnects tumoral cells with their microenvironment, but the effect of mechanosensing in acute myeloid leukemia (AML) blasts is poorly known. PIEZO1 perceives and transmits the constraints of the environment to human cells by acting as a non‐selective calcium channel, but very little is known about its role in leukemogenesis. Results For the first time, we show that PIEZO1 is preferentially expressed in healthy hematopoietic stem and progenitor cells in human hematopoiesis, and globally overexpressed in AML cells. In AML subtypes, PIEZO1 expression associates with favorable outcomes as better overall (OS) and disease‐free survival (DFS). If PIEZO1 is expressed and functional in THP1 leukemic myeloid cell line, its chemical activation doesn’t impact the proliferation, differentiation, nor survival of cells. However, the downregulation of PIEZO1 expression dramatically reduces the proliferation and the survival of THP1 cells. We show that PIEZO1 knock‐down blocks the cell cycle in G0/G1 phases of AML cells, impairs the DNA damage response pathways, and critically increases cell death by triggering extrinsic apoptosis pathways. Conclusions Altogether, our results reveal a new role for PIEZO1 mechanosensing in the survival and proliferation of leukemic blasts, which could pave the way for new therapeutic strategies to target AML cells.

Objectives To compare brain MRI findings in progressive multifocal leukoencephalopathy (PML) associated to rituximab and natalizumab treatments and HIV infection. Materials and methods In this retrospective, multicentric study, we analyzed brain MRI exams from 72 patients diagnosed with definite PML: 32 after natalizumab treatment, 20 after rituximab treatment, and 20 HIV patients. We compared T2- or FLAIR-weighted images, diffusion-weighted images, T2*-weighted images, and contrast enhancement features, as well as lesion distribution, especially gray matter involvement. Results The three PML entities affect U-fibers associated with low signal intensities on T2*-weighted sequences. Natalizumab-associated PML showed a punctuate microcystic appearance in or in the vicinity of the main PML lesions, a potential involvement of the cortex, and contrast enhancement. HIV and rituximab-associated PML showed only mild contrast enhancement, punctuate appearance, and cortical involvement. The CD4/CD8 ratio showed a trend to be higher in the natalizumab group, possibly mirroring a more efficient immune response. Conclusion Imaging features of rituximab-associated PML are different from those of natalizumab-associated PML and are closer to those observed in HIV-associated PML. Key Points • Nowadays, PML is emerging as a complication of new effective therapies based on monoclonal antibodies. • Natalizumab-associated PML shows more inflammatory signs, a perivascular distribution “the milky way,” and more cortex involvement than rituximab- and HIV-associated PML. • MRI differences are probably related to higher levels of immunosuppression in HIV patients and those under rituximab therapy.

The gene locus coordinates body patterning, hematopoiesis, and differentiation. While studying blood phenotype-associated variation within the locus, we identified a genetic variant, rs17437411, associated with globally reduced blood counts, protection from blood cancers, and variation in anthropometric phenotypes. We find that this variant disrupts the activity of a previously unstudied antisense long non-coding RNA (lncRNA) located between and , which we have named . The variant disrupts lncRNA function and reduces human hematopoietic stem cell (HSC) self-renewal. Mechanistically, enables appropriate expression and splicing of genes in HSCs, most notably , in an SRSF2-dependent manner. Given the critical role of gene expression in some blood cancers, we also demonstrate that variation or deletion compromises -dependent acute myeloid leukemias. Collectively, we show how insights from human genetic variation can uncover critical regulatory processes required for effective developmental gene expression.

Thrombosis remains a major cause of cardiovascular and cerebrovascular diseases, driven in large part by platelet activation and aggregation. Because platelets are continuously produced from hematopoietic stem cells (HSCs), durable reprogramming of HSC output offers a unique opportunity for a one-time antithrombotic intervention. Here, we show that DNA methylation-based epigenome editors delivered transiently as RNA result in stable, heritable gene silencing in primary human HSCs that persists through long-term self-renewal and megakaryocytic differentiation, while remaining reversible through targeted demethylation. Targeting the platelet integrin β3 ( ), this approach achieves robust, sustained repression and yields platelets with impaired aggregation. Extending this framework to additional genetically-nominated platelet targets establishes HSC epigenome editing as a durable and reversible strategy to modulate thrombotic risk and highlights broader opportunities to engineer hematopoiesis.

Most phenotype-associated genetic variants map to non-coding regulatory regions of the human genome. Moreover, variants associated with blood cell phenotypes are enriched in regulatory regions active during hematopoiesis. To systematically explore the nature of these regions, we developed a highly efficient strategy, Perturb-multiome, that makes it possible to simultaneously profile both chromatin accessibility and gene expression in single cells with CRISPR-mediated perturbation of a range of master transcription factors (TFs). This approach allowed us to examine the connection between TFs, accessible regions, and gene expression across the genome throughout hematopoietic differentiation. We discovered that variants within the TF-sensitive accessible chromatin regions, while representing less than 0.3% of the genome, show a ~100-fold enrichment in heritability across certain blood cell phenotypes; this enrichment is strikingly higher than for other accessible chromatin regions. Our approach facilitates large-scale mechanistic understanding of phenotype-associated genetic variants by connecting key -regulatory elements and their target genes within gene regulatory networks.