Prolonged haematologic toxicity in CAR-T-cell therapy: A review.

Chimeric antigen receptor-T-cell (CAR-T-cell) therapy is a novel immunotherapy with encouraging results for treatment of relapsed/refractory haematologic malignancies. With increasing use, our understanding of immune-mediated side effects such as cytokine release syndrome and neurotoxicity has improved; nevertheless, prolonged haematologic toxicity (PHT), with a high incidence rate, remains underrecognized. Owing to heterogeneity in populations, the CAR-T cells used and diseases treated as well as differences in the definition of PHT, its rate, risk factors and management vary across studies. In this review, we provide a narrative of PHT occurring in patients following CAR-T-cell therapy; evidence of PHT treatment strategies is also presented, with the aim of contributing to systematic understanding of PHT.

WISP2 downregulation inhibits the osteogenic differentiation of BMSCs in congenital scoliosis by regulating Wnt/ß-catenin pathway.

OBJECTIVES: Bone marrow mesenchymal stem cells (BMSCs) are instrumental in bone development, metabolism, and marrow microenvironment homeostasis. Despite this, the relevant effects and mechanisms of BMSCs on congenital scoliosis (CS) remain undefined. Herein, it becomes our focus to reveal the corresponding effects and mechanisms implicated. METHODS: BMSCs from CS patients (hereafter referred as CS-BMSCs) and healthy donors (NC-BMSCs) were observed and identified. Differentially expressed genes in BMSCs were analyzed utilizing scRNA-seq and RNA-seq profiles. The multi-differentiation potential of BMSCs following the transfection or infection was evaluated. The expression levels of factors related to osteogenic differentiation and Wnt/ß-catenin pathway were further determined as appropriate. RESULTS: A decreased osteogenic differentiation ability was shown in CS-BMSCs. Both the proportion of LEPR+ BMSCs and the expression level of WNT1-inducible-signaling pathway protein 2 (WISP2) were decreased in CS-BMSCs. WISP2 knockdown suppressed the osteogenic differentiation of NC-BMSCs, while WISP2 overexpression facilitated the osteogenesis of CS-BMSCs via acting on the Wnt/ß-catenin pathway. CONCLUSIONS: Our study collectively indicates WISP2 knockdown blocks the osteogenic differentiation of BMSCs in CS by regulating Wnt/ß-catenin signaling, thus providing new insights into the aetiology of CS.

Research progress on the hematopoietic microenvironment in aplastic anemia.

Aplastic anemia (AA) is a disease of bone marrow hematopoietic failure, and the main clinical manifestation is pancytopenia. Its pathogenesis is still unclear. In recent years, more research has been done on its immune abnormalities to explain its pathogenesis and less on the hematopoietic microenvironment, but there are still some advances. This article summarizes the research on the hematopoietic microenvironment of AA in recent years to provide new ideas for the clinical treatment of AA.

Whole-exome sequencing identifies FANC heterozygous germline mutation as an adverse factor for immunosuppressive therapy in Chinese aplastic anemia patients aged 40 or younger: a single-center retrospective study.

Acquired aplastic anemia (AA) is a bone marrow failure disorder characterized by pancytopenia, and immunosuppressive therapy (IST) is the optional first-line management. Several studies identified the influencing factors on IST response; however, there are still a considerable number of patients suffering from poor prognoses. In this study, we enrolled 61 AA patients aged ≤ 40 years old, and whole-exome sequencing (WES) found unexpected high FANC heterozygous germline mutations (28/61, 45.9%). Patients with FANC mutations have a significantly lower absolute reticulocyte count and CD34+ % in the bone marrow and also lower 3-, 6-, and 9-month IST response than that without mutation, which were 0% vs. 25% (P = 0.017), 26.3% vs. 42.1% (P = 0.495), and 29.4% vs. 72.2% (P = 0.011), especially in anti-thymocyte globulin combined with the cyclosporin A (ATG + CsA) group, which were 0% vs.33.4% (P = 0.143), 25% vs.83.3% (P = 0.103), and 25% vs. 100% (P = 0.003), respectively. The event-free survival in the FANCwt group was also better than that in the FANCmut group (P = 0.016) and also showed in patients who received ATG + CsA treatment (P = 0.045). In addition, all the adverse effects of FANC germline mutation were not significant in stem cell-transplanted group. Our result indicated that the WES-based detection of FANC heterozygous germline mutations may have a great meaning in predicting IST response of acquired AA. This study was registered at chictr.org.cn (# ChiCTR2100054992).

Bushen Jianpi Quyu Formula Alleviates Myelosuppression of an Immune-Mediated Aplastic Anemia Mouse Model via Inhibiting Expression of the PI3K/AKT/NF-κB Signaling Pathway.

Bushen Jianpi Quyu Formula (BSJPQYF), an experienced formula, has been used to treat aplastic anemia (AA) more than three decades. To determinate the effect of BSJPQYF on AA, we constructed an immune-mediated AA mouse model. All mice were divided into four groups: control, model, low dose (0.85 g/mL), and high dose (1.7 g/mL BSJPQYF) group. They were administered with different concentrations of BSJPQYF or normal saline for 14 days. Besides, components of BSJPQYF were analyzed by electrospray ionization and mass spectrometry (ESI-MS). Subsequently, mouse peripheral blood and femurs were collected, and bone marrow mesenchymal stem cells (BMSCs) were isolated by fluorescence-activated cell sorting (FACS). Among them, tumor necrosis factor-α (TNF-α), transforming growth factor-ß (TGF-ß), and interferon-γ (IFN-γ) were measured by ELISA assay, PI3K, AKT, p-AKT, NF-κB, p-NF-κB, TNF-α, and cleaved caspase-3 proteins were detected by western blot. Compared with standard compounds, we identified three compounds of BSJPQYF, namely, icariin, kaempferol and tanshinone iia, as potentially effective compounds for the treatment of AA. Through an in vivo study, we found the administration of BSJPQYF in high dose for 14 days could significantly increase peripheral blood count and bone marrow (BM) cells, meanwhile decrease TNF-α, TGF-ß, and IFN-γ levels. Besides, it could suppress the protein expression of PI3K and the phosphorylation of AKT and NF-κB to restrict the protein expression of TNF-α, eventually reduce the protein expression of cleaved caspase-3. This study demonstrated the therapeutic effects of BSJPQYF in AA, which could alleviate myelosuppression through inhibiting the expression of the PI3K/AKT/NF-κB signaling pathway.

Diagnosing MonoMAC Syndrome in GATA2 Germline Mutated Myelodysplastic Syndrome via Next-Generation Sequencing in a Patient with Refractory and Complex Infection: Case Report and Literature Review.

Monocytopenia and mycobacterial infection (MonoMAC) syndrome is a rare disease. Herein, we reported a 65-year-old Asian woman, previously diagnosed with myelodysplastic syndrome (MDS), suffering from recurrent pneumonia, intermittent fever, fatigue, and chest tightness lasting for five months. She was ultimately diagnosed with MonoMAC syndrome with Mycobacterium kansasii (M. kansasii) infection and GATA2 mutation through metagenomic generation sequencing (mNGS) of peripheral blood specimen, for which she was given anti-NTM therapy. Her situation significantly improved within 2 weeks of therapy. We discussed the clinical features, genetic characteristic, and prognosis of this disorder, aiming to further elucidate this rare syndrome. For MDS/AML patient with recurrent mixed infection and pancytopenia (especially with monocyte absence), MonoMAC syndrome should be highly suspected, and germline mutation and pathogen sequencing should be performed.