来自杂志 Blood 的文献。
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1.
小年 (2025-06-30 22:31):
#paper doi:10.1182/blood.2022016033 ,Kramer, M. H., et al. Proteomic and Phosphoproteomic Landscapes of Acute Myeloid Leukemia 研究团队对 44 例急性髓系白血病(AML)患者及 6 例健康对照样本进行蛋白质组和磷酸化蛋白质组分析,构建了包含 10,651 种蛋白质和 29,201 个磷酸化位点的数据库。发现 AML 中存在广泛的转录后调控,例如 IDH1/2 突变样本中 KDM4A/B/C 组蛋白去甲基化酶蛋白丰度显著升高,但 mRNA 水平无变化。NPMc 突变样本中,核导入蛋白 KPNA4 和 KPNB1 与突变体 NPMc 结合,可能参与异常核质运输。团队通过细胞膜蛋白筛选,鉴定出 CD180 和 MRC1/CD206 在 AML 细胞表面特异性高表达,为免疫治疗提供新靶点。磷酸化分析显示,FLT3-TKD 突变通过激活 SRC 家族激酶 FGR 和 HCK 促进增殖,PML-RARA 亚型呈现独特磷酸化特征,TP53 突变样本中 S183 位点磷酸化显著增加。该研究建立了首个整合蛋白质组与磷酸化蛋白质组的 AML 多组学数据库,揭示了转录后调控和信号通路异常的关键作用,提示 CD180、MRC1/CD206 及相关通路可作为潜在治疗靶点。
Blood, 2022-9-29. DOI: 10.1182/blood.2022016033
Abstract:
AbstractWe have developed a deep-scale proteome and phosphoproteome database from 44 representative acute myeloid leukemia (AML) patients from the LAML TCGA dataset and 6 healthy bone marrow–derived controls. After confirming … >>>
AbstractWe have developed a deep-scale proteome and phosphoproteome database from 44 representative acute myeloid leukemia (AML) patients from the LAML TCGA dataset and 6 healthy bone marrow–derived controls. After confirming data quality, we orthogonally validated several previously undescribed features of AML revealed by the proteomic data. We identified examples of posttranscriptionally regulated proteins both globally (ie, in all AML samples) and also in patients with recurrent AML driver mutations. For example, samples with IDH1/2 mutations displayed elevated levels of the 2-oxoglutarate–dependent histone demethylases KDM4A/B/C, despite no changes in messenger RNA levels for these genes; we confirmed this finding in vitro. In samples with NPMc mutations, we identified several nuclear importins with posttranscriptionally increased protein abundance and showed that they interact with NPMc but not wild-type NPM1. We identified 2 cell surface proteins (CD180 and MRC1/CD206) expressed on AML blasts of many patients (but not healthy CD34+ stem/progenitor cells) that could represent novel targets for immunologic therapies and confirmed these targets via flow cytometry. Finally, we detected nearly 30 000 phosphosites in these samples; globally, AML samples were associated with the abnormal phosphorylation of specific residues in PTPN11, STAT3, AKT1, and PRKCD. FLT3-TKD samples were associated with increased phosphorylation of activating tyrosines on the cytoplasmic Src-family tyrosine kinases FGR and HCK and related signaling proteins. PML-RARA–initiated AML samples displayed a unique phosphorylation signature, and TP53-mutant samples showed abundant phosphorylation of serine-183 on TP53 itself. This publicly available database will serve as a foundation for further investigations of protein dysregulation in AML pathogenesis. <<<
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2.
白鸟 (2023-04-29 23:16):
#paper Single-cell transcriptomics dissects hematopoietic cell destruction and T-cell engagement in aplastic anemia. Blood. 2021. 研究背景:再生障碍性贫血 (AA) 是一种T细胞介导的造血系统自身免疫性疾病,表现为造血干细胞和祖细胞 (HSPC) 的严重耗竭。异常活化的T淋巴细胞攻击自身造血干/祖细胞(HSPC)是再生障碍性贫血(AA)发病重要的机制。 研究难点:受限于技术和 HSPC 在骨髓衰竭背景下的稀疏性。AA患者骨髓残留HSPC细胞数量极少,精细剖析骨髓损伤后HSPC各组分的病理变化及T淋巴细胞免疫打击HSPC的分子机制比较困难。 样本类型:健康供体(healthy donors,n = 8)+ 非重度再生障碍性贫血患者 (non-SAA, n = 19) + 重度再生障碍性贫血患者 (SAA,  n = 4 );另加 药物处理组:免疫抑制治疗(IST)后患者 样本取样:骨髓及外周血中分选出CD34+造血干/祖细胞和CD4+/CD8+ T淋巴细胞 实验技术:STRT-Seq(高测序深度) + Smart-seq2 研究思路:不同疾病/健康组 -> 流式分选细胞 - > CD34+造血干/祖细胞和CD4+/CD8+ T淋巴细胞->单细胞测序(STRT-Seq + Smart-seq2)->定义了9类HSPC细胞亚群->基因表达和转录调控网络分析 研究结果: ① STRT-seq克服骨髓残留造血干细胞和祖细胞HSPC数量不足的限制,对AA患者的HSPC和T细胞进行分析,分别获得了2,385个HSPC和4,081个CD4+/CD8+ T细胞的单细胞转录组,定义了9类HSPCs细胞亚群,首次绘制了AA血液病理图谱,揭示了AA发病,特别是恶性转化的新机制。 ② AA中残留的HSPC在基因表达和转录调控网络中表现出谱系特异性的改变,提示存在谱系选择性造血损伤。 ③ 综合分析HSPC和T细胞的基因表达,确定了细胞类型特异性配体-受体相互作用是AA中免疫攻击的关键分子介质。 ④ 通过追踪免疫抑制治疗(IST)后的患者,发现HSPCs和T淋巴细胞的基因表达没有完全恢复到正常水平,甚至接近治疗前的状态,这可能是AA患者需要长期维持免疫抑制治疗的主要原因之一。
IF:21.000Q1 Blood, 2021-07-08. DOI: 10.1182/blood.2020008966 PMID: 33763704
Abstract:
Aplastic anemia (AA) is a T cell-mediated autoimmune disorder of the hematopoietic system manifested by severe depletion of the hematopoietic stem and progenitor cells (HSPCs). Nonetheless, our understanding of the … >>>
Aplastic anemia (AA) is a T cell-mediated autoimmune disorder of the hematopoietic system manifested by severe depletion of the hematopoietic stem and progenitor cells (HSPCs). Nonetheless, our understanding of the complex relationship between HSPCs and T cells is still obscure, mainly limited by techniques and the sparsity of HSPCs in the context of bone marrow failure. Here we performed single-cell transcriptome analysis of residual HSPCs and T cells to identify the molecular players from patients with AA. We observed that residual HSPCs in AA exhibited lineage-specific alterations in gene expression and transcriptional regulatory networks, indicating a selective disruption of distinct lineage-committed progenitor pools. In particular, HSPCs displayed frequently altered alternative splicing events and skewed patterns of polyadenylation in transcripts related to DNA damage and repair, suggesting a likely role in AA progression to myelodysplastic syndromes. We further identified cell type-specific ligand-receptor interactions as potential mediators for ongoing HSPCs destruction by T cells. By tracking patients after immunosuppressive therapy (IST), we showed that hematopoiesis remission was incomplete accompanied by IST insensitive interactions between HSPCs and T cells as well as sustained abnormal transcription state. These data collectively constitute the transcriptomic landscape of disrupted hematopoiesis in AA at single-cell resolution, providing new insights into the molecular interactions of engaged T cells with residual HSPCs and render novel therapeutic opportunities for AA. <<<
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3.
小年 (2023-04-29 17:35):
#paper DOI: 10.1182/blood.2020006287. Tumor-intrinsic and -extrinsic determinants of response to blinatumomab in adults with B-ALL. Blood. 2021 Jan 28;137(4):471-484. 通过对肿瘤和免疫细胞的综合基因组分析,证明肿瘤内在和外在因素都会影响患者对blinatumomab(博纳吐单抗治疗)的反应。 单细胞测序研究了44位采用blinatumomab治疗的复发性/难治性B-ALL成人患者(包括2例MRD阳性的患者)。 血液病患者的总体缓解率为 55%,CRLF2 重排费城染色体样 ALL 患者(Ph样ALL)的缓解率很高(12 [75%] of 16)。 转录组结果来看,应答者的预处理样本在肿瘤内表现出免疫应答增强。在治疗期间,外显子CD19 ex2part的外显子剪接亚型的表达增加与治疗失败有关。 未来的研究可评估使用ex2part作为CD19定向免疫疗法(包括blinatumomab和CAR19)反应的生物标志物。
IF:21.000Q1 Blood, 2021-01-28. DOI: 10.1182/blood.2020006287 PMID: 32881995
Abstract:
Blinatumomab, a bispecific antibody that directs CD3+ T cells to CD19+ tumor cells, shows variable efficacy in B-progenitor acute lymphoblastic leukemia (B-ALL). To determine tumor-intrinsic and -extrinsic determinants of response, … >>>
Blinatumomab, a bispecific antibody that directs CD3+ T cells to CD19+ tumor cells, shows variable efficacy in B-progenitor acute lymphoblastic leukemia (B-ALL). To determine tumor-intrinsic and -extrinsic determinants of response, we studied 44 adults with relapsed or refractory B-ALL (including 2 minimal residual disease positive) treated with blinatumomab using bulk tumor and single-cell sequencing. The overall response rate in patients with hematological disease was 55%, with a high response rate in those with CRLF2-rearranged Philadelphia chromosome-like ALL (12 [75%] of 16). Pretreatment samples of responders exhibited a tumor-intrinsic transcriptomic signature of heightened immune response. Multiple mechanisms resulted in loss of CD19 expression, including CD19 mutations, CD19-mutant allele-specific expression, low CD19 RNA expression, and mutations in CD19 signaling complex member CD81. Patients with low hypodiploid ALL were prone to CD19- relapse resulting from aneuploidy-mediated loss of the nonmutated CD19 allele. Increased expression of a CD19 isoform with intraexonic splicing of exon 2, CD19 ex2part, at baseline or during therapy was associated with treatment failure. These analyses demonstrate both tumor-intrinsic and -extrinsic factors influence blinatumomab response. We show that CD19 mutations are commonly detected in CD19- relapse during blinatumomab treatment. Identification of the CD19 ex2part splice variant represents a new biomarker predictive of blinatumomab therapy failure. <<<
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