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•Reduced YAP1 expression suppresses thrombopoiesis through cytoskeletal actin misalignment in MKs, causing thrombocytopenia during ITP.•YAP1, regulated by GATA-binding protein 1, cooperates with myosin heavy chain 9 to reach actin reorganization, facilitating thrombopoiesis.

•EMD mimics the architectural complexity of solid tumors, marked by diverse microenvironments, multiclonality, and TNFRSF17and GPRC5Dlevels.•EMD shows infiltration of active T cells spatially confined to niches segregated from MM cells, potentially affecting the therapeutic response.

•PV with or without rituximab was tested in relapsed/refractory CLL, including after progression during treatment with a covalent BTKi.•These fixed-duration treatments were safe and showed promising efficacy in both covalent BTK-naïve and BTK-exposed patients.

•Lufaxin inhibits complement in assays of aHUS and PNH as well as thrombin generation in plasma.•Lufaxin binds the C3 proconvertase of the alternative pathway and fXa at different sites, allowing simultaneous inhibition.

Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is a protein tyrosine phosphatase that negatively regulates T-cell signaling. However, whether it is expressed and functions in platelets remains unknown. Here we investigated the expression and role of PTPN22 in platelet function. We reported PTPN22 expression in both human and mouse platelets. Using PTPN22−/− mice, we showed that PTPN22 deficiency significantly shortened tail-bleeding time and accelerated arterial thrombus formation without affecting venous thrombosis and the coagulation factors VIII and IX. Consistently, PTPN22-deficient platelets exhibited enhanced platelet aggregation, granule secretion, calcium mobilization, lamellipodia formation, spreading, and clot retraction. Quantitative phosphoproteomic analysis revealed the significant difference of phosphodiesterase 5A (PDE5A) phosphorylation in PTPN22-deficient platelets compared with wild-type platelets after collagen-related peptide stimulation, which was confirmed by increased PDE5A phosphorylation (Ser92) in collagen-related peptide–treated PTPN22-deficient platelets, concomitant with reduced level and vasodilator-stimulated phosphoprotein phosphorylation (Ser157/239). In addition, PTPN22 interacted with phosphorylated PDE5A (Ser92) and dephosphorylated it in activated platelets. Moreover, purified PTPN22 but not the mutant form (C227S) possesses intrinsic serine phosphatase activity. Furthermore, inhibition of PTPN22 enhanced human platelet aggregation, spreading, clot retraction, and increased PDE5A phosphorylation (Ser92). In conclusion, our study shows a novel role of PTPN22 in platelet function and arterial thrombosis, identifying new potential targets for future prevention of thrombotic or cardiovascular diseases.

Hemogen is a hematopoietic tissue–specific gene that regulates the proliferation and differentiation of hematopoietic cells; however, the mechanism underlying its function in erythropoiesis is unknown. We found that depletion of hemogen in human CD34+ erythroid progenitor cells and HUDEP2 cells significantly reduced the expression of genes associated with heme and hemoglobin synthesis, supporting a positive role for hemogen in erythroid maturation. In human K562 cells, hemogen antagonized the occupancy of corepressors nucleosome remodeling and histone deacetylase (NuRD) complex and facilitated LDB1 complex–mediated chromatin looping. Hemogen recruited SWI/SNF complex ATPase BRG1 as a coactivator to regulate nucleosome accessibility and H3K27ac enrichment for promoter and enhancer activity. To determine whether hemogen/BRG1 cooperativity is conserved in mammalian systems, we generated hemogen-knockout/knockin mice and investigated hemogen/BRG1 function in murine erythropoiesis. Loss of hemogen in embryonic days 12.5 to 16.5 fetal liver cells impeded erythroid differentiation through reducing the production of mature erythroblasts. Chromatin immunoprecipitation sequencing in wild-type and hemogen-knockout animals revealed that BRG1 is largely dependent on hemogen to regulate chromatin accessibility at erythroid gene promoters and enhancers. In summary, the hemogen/BRG1 interaction in mammals is essential for fetal erythroid maturation and hemoglobin production through its active role in promoter and enhancer activity and chromatin organization.

The Kasabach-Merritt phenomenon (KMP) in kaposiform hemangioendothelioma (KHE) is characterized by life-threatening thrombocytopenia and consumptive coagulopathy. This study compared the efficacy and safety of sirolimus plus prednisolone vs sirolimus monotherapy as treatment strategies for KHE with KMP in the largest cohort to date. Participants were randomized to receive either sirolimus in combination with a short course of prednisolone or sirolimus monotherapy for at least 12 months. The primary outcome was defined as achievement of a durable platelet response (platelet count >100 × 109/L) at week 4. Participants completed efficacy assessments 2 years after the initial treatment. At week 4, a durable platelet response was achieved by 35 of 37 patients given sirolimus and prednisolone compared with 24 of 36 patients given sirolimus monotherapy (difference 27.9%; 95% confidence interval, 10.0-44.7). Compared with the sirolimus monotherapy group, the combination treatment group showed improvements in terms of measures of durable platelet responses at all points during the initial 3-week treatment period, median platelet counts during weeks 1 to 4, increased numbers of patients achieving fibrinogen stabilization at week 4, and objective lesion responses at month 12. Patients receiving combination therapy had fewer blood transfusions and a lower total incidence of disease sequelae than patients receiving sirolimus alone. The frequencies of total adverse events and grade 3-4 adverse events during treatment were similar in both groups. The responses seen in patients with KHE with KMP were profound and encouraging, suggesting that sirolimus plus prednisolone should be considered a valid treatment of KHE with KMP. This trial was registered at www.clinicaltrials.gov as #NCT03188068.

1.Hepatocyte-specific Notch1deficiency impairs hepatic thrombopoietin production and reduces circulating platelet number.2.Dll4 on desialylated platelets activates hepatocyte Notch1 signaling and upregulates HES5 expression, leading to JAK2/STAT3 phosphorylation.

Cereblon is the direct binding target of the immunomodulatory drugs (IMiDs) that are commonly used to treat multiple myeloma (MM), the second most frequent hematologic malignancy. Patients respond well to initial treatment with IMiDs, but virtually all patients develop drug resistance over time, and the underlying mechanisms are poorly understood. We identified an as yet undescribed DNA hypermethylation in an active intronic CRBN enhancer. Differential hypermethylation in this region was found to be increased in healthy plasma cells, but was more pronounced in IMiD-refractory MM. Methylation significantly correlated with decreased CRBN expression levels. DNA methyltransferase inhibitor (DNTMi) in vitro experiments induced CRBN enhancer demethylation, and sensitizing effects on lenalidomide treatment were observed in 2 MM cell lines. Thus, we provide first evidence that aberrant CRBN DNA methylation is a novel mechanism of IMiD resistance in MM and may predict IMiD response prior to treatment.

Our previous clinical study showed that low-dose decitabine exhibited sustained responses in nearly half of patients with refractory immune thrombocytopenia (ITP). The long-term efficacy of decitabine in ITP is not likely due to its simple role in increasing platelet production. Whether decitabine has the potential to restore immune tolerance in ITP is unknown. In this study, we analyzed the effect of decitabine on T-cell subpopulations in ITP in vitro and in vivo. We found that low-dose decitabine promoted the generation and differentiation of regulatory T (Treg) cells and augmented their immunosuppressive function. Splenocytes from CD61 knockout mice immunized with CD61+ platelets were transferred into severe combined immunodeficient mouse recipients to induce a murine model of ITP. Low-dose decitabine alleviated thrombocytopenia and restored the balance between Treg and helper T (Th) cells in active ITP mice. Treg deletion and depletion offset the effect of decitabine in restoring CD4+ T-cell subpopulations in ITP mice. For patients who received low-dose decitabine, the quantity and function of Treg cells were substantially improved, whereas Th1 and Th17 cells were suppressed compared with the pretreatment levels. Next-generation RNA-sequencing and cytokine analysis showed that low-dose decitabine rebalanced T-cell homeostasis, decreased proinflammatory cytokines, and downregulated phosphorylated STAT3 in patients with ITP. STAT3 inhibition analysis suggested that low-dose decitabine might restore Treg cells by inhibiting STAT3 activation. In conclusion, our data indicate that the immunomodulatory effect of decitabine provides one possible mechanistic explanation for the sustained response achieved by low-dose decitabine in ITP.

High-risk B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive disease, often characterized by resistance to chemotherapy. A frequent feature of high-risk B-ALL is loss of function of the IKAROS (encoded by the IKZF1 gene) tumor suppressor. Here, we report that IKAROS regulates expression of the BCL2L1 gene (encodes the BCL-XL protein) in human B-ALL. Gain-of-function and loss-of-function experiments demonstrate that IKAROS binds to the BCL2L1 promoter, recruits histone deacetylase HDAC1, and represses BCL2L1 expression via chromatin remodeling. In leukemia, IKAROS’ function is impaired by oncogenic casein kinase II (CK2), which is overexpressed in B-ALL. Phosphorylation by CK2 reduces IKAROS binding and recruitment of HDAC1 to the BCL2L1 promoter. This results in a loss of IKAROS-mediated repression of BCL2L1 and increased expression of BCL-XL. Increased expression of BCL-XL and/or CK2, as well as reduced IKAROS expression, are associated with resistance to doxorubicin treatment. Molecular and pharmacological inhibition of CK2 with a specific inhibitor CX-4945, increases binding of IKAROS to the BCL2L1 promoter and enhances IKAROS-mediated repression of BCL2L1 in B-ALL. Treatment with CX-4945 increases sensitivity to doxorubicin in B-ALL, and reverses resistance to doxorubicin in multidrug-resistant B-ALL. Combination treatment with CX-4945 and doxorubicin show synergistic therapeutic effects in vitro and in preclinical models of high-risk B-ALL. Results reveal a novel signaling network that regulates chemoresistance in leukemia. These data lay the groundwork for clinical testing of a rationally designed, targeted therapy that combines the CK2 inhibitor, CX-4945, with doxorubicin for the treatment of hematopoietic malignancies.

Anemic stress induces stress erythropoiesis, which rapidly generates new erythrocytes to restore tissue oxygenation. Stress erythropoiesis is best understood in mice where it is extramedullary and occurs primarily in the spleen. However, both human and mouse stress erythropoiesis use signals and progenitor cells that are distinct from steady-state erythropoiesis. Immature stress erythroid progenitors (SEPs) are derived from short-term hematopoietic stem cells. Although the SEPs are capable of self-renewal, they are erythroid restricted. Inflammation and anemic stress induce the rapid proliferation of SEPs, but they do not differentiate until serum erythropoietin (Epo) levels increase. Here we show that rather than directly regulating SEPs, Epo promotes this transition from proliferation to differentiation by acting on macrophages in the splenic niche. During the proliferative stage, macrophages produce canonical Wnt ligands that promote proliferation and inhibit differentiation. Epo/Stat5-dependent signaling induces the production of bioactive lipid mediators in macrophages. Increased production of prostaglandin J2 (PGJ2) activates peroxisome proliferator-activated receptor γ (PPARγ)-dependent repression of Wnt expression, whereas increased production of prostaglandin E2 (PGE2) promotes the differentiation of SEPs.

Although no therapies are approved for light chain (AL) amyloidosis, cyclophosphamide, bortezomib, and dexamethasone (CyBorD) is considered standard of care. Based on outcomes of daratumumab in multiple myeloma (MM), the phase 3 ANDROMEDA study (NCT03201965) is evaluating daratumumab-CyBorD vs CyBorD in newly diagnosed AL amyloidosis. We report results of the 28-patient safety run-in. Patients received subcutaneous daratumumab (DARA SC) weekly in cycles 1 to 2, every 2 weeks in cycles 3 to 6, and every 4 weeks thereafter for up to 2 years. CyBorD was given weekly for 6 cycles. Patients had a median of 2 involved organs (kidney, 68%; cardiac, 61%). Patients received a median of 16 (range, 1-23) treatment cycles. Treatment-emergent adverse events were consistent with DARA SC in MM and CyBorD. Infusion-related reactions occurred in 1 patient (grade 1). No grade 5 treatment-emergent adverse events occurred; 5 patients died, including 3 after transplant. Overall hematologic response rate was 96%, with a complete hematologic response in 15 (54%) patients; at least partial response occurred in 20, 22, and 17 patients at 1, 3, and 6 months, respectively. Renal response occurred in 6 of 16, 7 of 15, and 10 of 15 patients, and cardiac response occurred in 6 of 16, 6 of 13, and 8 of 13 patients at 3, 6, and 12 months, respectively. Hepatic response occurred in 2 of 3 patients at 12 months. Daratumumab-CyBorD was well tolerated, with no new safety concerns versus the intravenous formulation, and demonstrated robust hematologic and organ responses. This trial was registered at www.clinicaltrials.govas #NCT03201965.

Internal tandem duplication (ITD) mutations within the FMS-like receptor tyrosine kinase-3 (FLT3) can be found in up to 25% to 30% of acute myeloid leukemia (AML) patients and confer a poor prognosis. Although FLT3 tyrosine kinase inhibitors (TKIs) have shown clinical responses, they cannot eliminate primitive FLT3-ITD+ AML cells, which are potential sources of relapse. Therefore, elucidating the mechanisms underlying FLT3-ITD+ AML maintenance and drug resistance is essential to develop novel effective treatment strategies. Here, we demonstrate that FLT3 inhibition induces histone deacetylase 8 (HDAC8) upregulation through FOXO1- and FOXO3-mediated transactivation in FLT3-ITD+ AML cells. Upregulated HDAC8 deacetylates and inactivates p53, leading to leukemia maintenance and drug resistance upon TKI treatment. Genetic or pharmacological inhibition of HDAC8 reactivates p53, abrogates leukemia maintenance, and significantly enhances TKI-mediated elimination of FLT3-ITD+ AML cells. Importantly, in FLT3-ITD+ AML patient–derived xenograft models, the combination of FLT3 TKI (AC220) and an HDAC8 inhibitor (22d) significantly inhibits leukemia progression and effectively reduces primitive FLT3-ITD+ AML cells. Moreover, we extend these findings to an AML subtype harboring another tyrosine kinase–activating mutation. In conclusion, our study demonstrates that HDAC8 upregulation is an important mechanism to resist TKIs and promote leukemia maintenance and suggests that combining HDAC8 inhibition with TKI treatment could be a promising strategy to treat FLT3-ITD+ AML and other tyrosine kinase mutation–harboring leukemias.

Internal tandem duplication (ITD) mutations within the FMS-like receptor tyrosine kinase-3 (FLT3) can be found in up to 25% to 30% of acute myeloid leukemia (AML) patients and confer a poor prognosis. Although FLT3 tyrosine kinase inhibitors (TKIs) have shown clinical responses, they cannot eliminate primitive FLT3-ITD+AML cells, which are potential sources of relapse. Therefore, elucidating the mechanisms underlying FLT3-ITD+AML maintenance and drug resistance is essential to develop novel effective treatment strategies. Here, we demonstrate that FLT3 inhibition induces histone deacetylase 8 (HDAC8) upregulation through FOXO1- and FOXO3-mediated transactivation in FLT3-ITD+AML cells. Upregulated HDAC8 deacetylates and inactivates p53, leading to leukemia maintenance and drug resistance upon TKI treatment. Genetic or pharmacological inhibition of HDAC8 reactivates p53, abrogates leukemia maintenance, and significantly enhances TKI-mediated elimination of FLT3-ITD+AML cells. Importantly, in FLT3-ITD+AML patient–derived xenograft models, the combination of FLT3 TKI (AC220) and an HDAC8 inhibitor (22d) significantly inhibits leukemia progression and effectively reduces primitive FLT3-ITD+AML cells. Moreover, we extend these findings to an AML subtype harboring another tyrosine kinase–activating mutation. In conclusion, our study demonstrates that HDAC8 upregulation is an important mechanism to resist TKIs and promote leukemia maintenance and suggests that combining HDAC8 inhibition with TKI treatment could be a promising strategy to treat FLT3-ITD+AML and other tyrosine kinase mutation–harboring leukemias.

•CM-TMA has a classical pathway stimulus driven by polyreactive IgM, addressing why 40% of CM-TMA lack complement-specific variants.•Complement biosensors can be used to monitor classical and alternative pathway activity and aid in the diagnosis of CM-TMA.

•A new TCR-mimic monoclonal antibody specific for the WT1-derived epitope RMF presented by HLA-A2, ESK2, was developed.•ESK2 was engineered into a new CAR T format, AbTCR-CSR, which comprises primary and CSR, directed against 2 antigens, WT1 and CD33 in AML.

Introduction:Patients (pts) with advanced and heavily pretreated relapsed/refractory multiple myeloma (RRMM) have worse health-related quality of life (HRQoL) than those at earlier stages of the disease and have limited treatment options available to enable improvement in HRQoL, particularly those who are triple-class exposed. Talquetamab (tal), a novel GPRC5D×CD3 bispecific antibody, has shown deep and durable responses in the MonumenTAL-1 study (NCT03399799/NCT04634552) in pts with RRMM. Here, we report patient-reported outcomes (PROs) from the MonumenTAL-1 study, focusing on data through cycle 21 from the tal 0.4 mg/kg weekly (QW) dosing cohort (initial results presented at ASH 2022) and new data through cycle 15 from the tal 0.8 mg/kg every other week (Q2W) dosing cohort.

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Background:Chimeric Antigen Receptor (CAR) T cell therapy in patients with hematologic malignancies is limited by immune-related toxicities such as Cytokine Release Syndrome (CRS) in over 30% of patients, whereas no CRS was observed in patients receiving NK cell therapy. CRS is characterized by an early phase with fever, hypotension, and elevations of cytokines, including IFN-γ, GM-CSF, TNF-α , IL-10, and IL-6.

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OBJECTIVES:Eltrombopag (EPAG) was initially approved by the U.S. Food and Drug Administration (FDA) as first-line treatment, combined with standard immunosuppressive therapy, for patients older than two years old with severe aplastic anemia (SAA). However, the use of EPAG in children with different types of aplastic anemia (AA), especially non-severe AA (NSAA) has been limited. Therefore, we decided to investigate the efficacy, safety, and pharmacokinetics of EPAG in children with NSAA, SAA, and very severe AA (VSAA).

Background:There are a lack of clinical prediction tools in early-stage Hodgkin lymphoma (E-HL). We developed and validated a modern-day model, known as E-HIPI, to predict progression-free survival (PFS) within the first 5 years (y) incorporating detailed individual patient (pt) data from international clinical trials and prospective registry data that were standardized, normalized & harmonized as part of the HoLISTIC Consortium (www.hodgkinconsortium.org).

Introduction

BackgroundCX-4945 is an ATP-competitive inhibitor of CK2, which is currently being used in clinical trials to treat various cancer types. Chidamide (CHI), a novel histone deacetylase inhibitor (HDACi), is now involved in the salvage treatment of relapsed/refractory acute myeloid leukemia (AML) in a clinical trial. The anti-leukemia effects of either single drug have been reported by inducing cell apoptosis through suppressing multi-oncogenic pathways in human tumor cells. However, whether and how the combination of the two drugs exerts synergistic anti-tumor effects remains undetermined. This study is to investigate the synergistic therapeutic effects of CX-4945 in combination with CHI in AML.

Introduction:Activation of the Hedgehog signaling pathway has been correlated with the development and disease progression of myeloid leukemia. This Phase I clinical trial aimed to evaluate the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), safety and tolerability of GT1708F in patients with myeloid malignancies.

Introduction:Novel T-cell redirecting therapies (TCR), including chimeric antigen receptor T-cell therapy (CAR-T) and bispecific antibodies (BsAbs), are important new treatment options for patients (pts) with relapsed/refractory multiple myeloma (RRMM) but result in a new unmet need for pts who relapse following these therapies. Talquetamab is the most advanced BsAb therapy targeting G protein-coupled receptor family C group 5 member D (GPRC5D), a novel antigen that is overexpressed on malignant plasma cells but is expressed at low levels on B cells and bone marrow progenitors. Previous results from the phase 1/2 MonumenTAL-1 study (NCT03399799/NCT04634552) demonstrated deep and durable responses with talquetamab in pts with RRMM, with an overall response rate (ORR) of >71% in 288 pts naive to TCR and 65% in 51 pts with prior TCR. Here, we present updated results in pts with prior TCR, including an additional 19 pts enrolled since the prior analysis.

Background:

Myelofibrosis is a type of myeloproliferative disorder, and research indicates that the immunosuppressive tumor microenvironment plays a significant role in the pathogenesis of myelofibrosis, with myeloid-derived suppressor cells (MDSCs) being the primary inhibitory cells involved in shaping the tumor immune microenvironment. In this study, we used flow cytometry to detect the number of MDSCs in the bone marrow of myelofibrosis patients and revealed the relationship between MDSCs and gene expression levels through single-cell transcriptome sequencing.

Background:The optimal management of patients with primary mediastinal B-cell lymphoma (PMBCL) who experience a partial metabolic response (PMR) on FDG-PET after initial systemic therapy is unclear. This study aimed to investigate different management strategies and outcomes for PMBCL patients who achieved PMR following primary systemic therapy, utilizing a single-center retrospective design.

INTRODUCTION:T-cell malignancies are associated with frequent relapse and high morbidity in children and adults, partly due to the lack of effective or targeted treatment options. Despite the use of multidrug chemotherapy, <50% of adults and <75% of children with T-ALL survive longer than five years. While CAR-T cell therapy is remarkable in treating B-cell malignancies, its use in T-cell malignancies is restricted due to fratricide, risk of immunodeficiency, and immune escape.

The molecular drivers of classic Hodgkin lymphoma (HL) underlying its pathologic and clinical distinctions from non-Hodgkin lymphoma (NHL) have been challenging to uncover. The study of HL has been impeded by the rarity of the Hodgkin-Reed-Sternberg (HRS) cells within a dense tumor microenvironment (TME). Previously, we developed a FACS approach to isolate the HRS cells and profiled their whole exomes and genomes (Reichel et al 2015; Maura et al 2023). These studies did not reveal an HRS-specific mutational signature, but rather mutations that overlap with those of NHL, such as those in SOCS1and HIST1H1E. These data suggested that non-genetic factors such as the underlying cell state may cooperate with somatic mutations to induce HL. However, we previously lacked the ability to co-map somatic mutations and cell states within the same cancer cells. We thus developed Genotyping of Transcriptomes (GoT; Nam et al 2019) that links single-cell RNA-seq (scRNA-seq) and somatic mutations within the same thousands of individual cells. We applied GoT to primary HL samples (n = 10 HL; 68291 cells, Fig. 1A) after FACS-isolation of HRS cells.

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Background: Serotherapies such as anti-thymocyte globulin (ATG) and alemtuzumab (AL) are added to conditioning chemotherapy for matched related donor (MRD) hematopoietic cell transplantation (HCT) for sickle cell disease (SCD) to facilitate engraftment and prevent graft-vs-host disease (GVHD). Most reports show ATG added to myeloablative (MA) conditioning; however, the use of AL has increased with investigation of different intensity regimens. The aim of this study was to compare HCT-related outcomes across common conditioning approaches to determine superiority.

Sickle cell disease (SCD) is an inherited hemoglobin (Hb) disorder which leads to significant morbidity and early mortality. Hematopoietic cell transplantation (HCT) is the only curative treatment with long-term outcome data, demonstrating excellent symptom-free survival particularly when a matched related donor (MRD) is available. Most MRD have sickle cell trait (Hb AS), but trait donor HCT is considered acceptable by the FDA and without negative impact. Further, initial gene addition and editing approaches for SCD have resulted in a trait-like status with benefit. Sickle trait, however, is associated with complications such as papillary necrosis, bacteriuria, splenic infarction, and exercise-induced death. The primary aim of this study was to compare long-term outcomes following MRD HCT for SCD based on donor Hb genotype, to objectively describe any impact on outcomes.

Background:Umbilical cord blood transplantation (UCBT) is a curable therapy for hematological disease; however, the impact of nutritional status on UCBT outcomes remains controversial. To evaluate the joint effect of clinical characteristics and nutritional status on the prognosis of patients who underwent UCBT, we screened various factors to establish a predictive model of overall survival (OS) after UCBT.

BackgroundThe inferior effect of rATG is due to the early fatal blow caused by the more potent immunosuppression. In order to retain its sustainable immunosuppression while weakening the early fatal blow. We explored a modifying schedule of administration of rATG by prolonging the course of rATG administration based on the equality of total dose, and then reported the better response and survival in severe aplastic anemia (SAA). And previously, we reported the encouraging effectiveness of cyclosporine alternately combined with levamisole (CSA and LMS regimen) in moderate AA, refractory or relapsed SAA, and SAA. We aim to establish whether the optimized rATG protocol plus sequential CSA and LMS regimen could improve SAA outcomes.

Background:Previous studies have verified the dysfunction of mesenchymal stem cells (MSCs) for immunoregulation in acquired aplastic anemia (AA) patients. Exosomes derived from MSCs can partially substitute MSC acting as immune regulator. Dysfunction of exosomes (Exos) derived from AA-MSC ( AA-Exos) may play a key role in immunologic dissonance.