Hematology最新文献

Objectives: Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder caused by increased platelet destruction and altered production. Despite the well-described pathophysiological background of immune dysregulation, current treatment guidelines consist of monotherapy with different drugs, with no tool to predict which patient is more suitable for each therapeutic modality.

Methods: In our study, we attempted to determine differences in the immune setting, comparing the patients' responses to administered therapy. During 12-month follow-up, we assessed blood count, antiplatelet autoantibodies, and T lymphocyte subsets in peripheral blood in 35 patients with ITP (newly diagnosed or relapsed disease).

Results: Our data show that the value of antiplatelet autoantibodies, the percentage of cytotoxic T lymphocytes, and the immunoregulatory index (IRI, CD4+ / CD8+ T cell ratio) differ significantly by treatment response. Responders have a higher IRI (median 2.1 vs. 1.5 in non-responders, P = 0.04), higher antiplatelet autoantibodies (median 58 vs. 20% in non-responders, P = 0.01) and lower relative CD8+ T cells count (P = 0.02) before treatment.

Discussion: The results suggest that immunological parameters (antiplatelet autoantibodies, relative CD8+ T cell count and IRI) could be used as prognostic tools for a worse clinical outcome in patients with ITP.

Conclusion: These biomarkers could be utilized for stratification and eventually selection of treatment preferring combination therapy.

The ability to perform hematopoietic cell transplant across major histocompatibility complex barriers can dramatically increase the availability of donors and allow more patients across the world to pursue curative transplant procedures for underlying hematologic disorders. Early attempts at haploidentical transplantation using broadly reactive T-cell depletion approaches were compromised by graft rejection, graft-versus-host disease and prolonged immune deficiency. The evolution of haploidentical transplantation focused on expanding transplanted hematopoietic progenitors as well as using less broadly reactive T-cell depletion. Significant outcome improvements were identified with technology advances allowing selective depletion of donor allospecific T cells, initially ex-vivo with evolution to its current in-vivo approach with the infusion of the highly immunosuppressive chemotherapy agent, cyclophosphamide after transplantation procedure. Current approaches are facile and portable, allowing expansion of allogeneic hematopoietic cell transplantation for patients across the world, including previously underserved populations.

Objectives: Constitutive activation of Janus kinase 2 (JAK2)/signal transducer and activator of transcription (STAT) signaling pathway is central to the pathogenesis of myeloproliferative neoplasms (MPNs). Long noncoding RNAs (lncRNAs) regulate diverse biological processes. However, the role of lncRNAs in MPN pathogenesis is not well studied.

Methods: The expression of lnc-AC004893 in MPN patients was measured by quantitative real-time PCR (qRT-PCR). Gene-specific short hairpin RNAs (shRNAs) were designed to inhibit the expression of lnc-AC004893, and western blot was performed to explore the role of lnc-AC004893 via regulating the JAK2/STAT5 signaling pathway. Furthermore, co-IP was performed to determine the binding ability of lnc-AC004893 and STAT5 protein. Finally, the BaF3-JAK2V617F-transplanted mouse model was used to assess the biological role of lnc-ac004893 in vivo.

Results: We report that lnc-AC004893, a poorly conserved pseudogene-209, is substantially upregulated in MPN cells compared with normal controls (NCs). Knockdown of lnc-AC004893 by specific shRNAs suppressed cell proliferation and decreased colony formation. Furthermore, the knockdown of lnc-AC004893 reduced the expression of p-STAT5 but not total STAT5 in HEL and murine IL-3-dependent Ba/F3 cells, which present constitutive and inducible activation of JAK2/STAT5 signaling. In addition, inhibition of murine lnc-ac004893 attenuated BaF3-JAK2V617F-transplanted phenotypes and extended the overall survival. Mechanistically, knockdown of lnc-AC004893 enhanced the binding ability of STAT5 and protein tyrosine phosphatase SHP1. Furthermore, knockdown of lnc-AC004893 decreased STAT5-lnc-AC004893 interaction but not SHP1-lnc-AC004893 interaction.

Conclusion: Lnc-AC004893 regulates STAT5 phosphorylation by affecting the interaction of STAT5 and SHP1. Lnc-AC004893 might be a potential therapeutic target for MPN patients.

Background: Chronic myelomonocytic leukemia is a clonal hematological disorder with an inherent risk of transformation to acute myeloid leukemia. Recently, there has been exponential discovery of molecular abnormalities in patients with chronic myelomonocytic leukemia. Some of these mutations independently contribute to a higher risk of transformation and result in inferior overall survival. Treatment strategies for patients undergoing blastic transformation in chronic myelomonocytic leukemia, especially after progressing on hypomethylating agents, are currently limited.Case presentation: We present a case of a 70-year-old male patient with chronic myelomonocytic leukemia blastic transformation with RUNX1 mutation following azacitidine monotherapy. Notably, he achieved hematological complete remission after the first course of venetoclax plus azacitidine, leading to the disappearance of RUNX1 mutation. We performed serial assessments of molecular analysis by next generation sequencing throughout his clinical course.Conclusion: The presence of RUNX1 mutation is associated with higher response rates to venetoclax-based combination therapies in chronic myelomonocytic leukemia with blastic transformation. Our findings suggest that even after azacitidine monotherapy, venetoclax plus azacitidine is effective in targeting leukemic clones harboring RUNX1 mutations. Furthermore, we emphasize the significance of molecular analysis, including next-generation sequencing, in providing insights into the detailed dynamics of clonal evolution and guiding treatment decisions.

Objective: To analyze the efficacy of daratumumab-based regimen in newly diagnosed multiple myeloma(NDMM) patients with paraskeletal plasmacytomas (PPs).

Methods: The medical data of 28 NDMM patients with PPs were retrospectively analyzed. The daratumumab-based regimen was divided into group A, and the daratumumab-free regimen was divided into group B. The risk factors, efficacy, and overall survival (OS) were compared between the two groups.

Results: The results of univariate COX regression analysis showed that only the grouping and creatinine were statistically significant. The HR value of group A was 0.30(0.10-0.88, p = 0.029), which was a protective factor for patient survival, and the HR value of creatinine was 1.00(1.00-1.01, p = 0.026), which was a risk factor for patient survival. There was a statistically significant difference in efficacy between the two groups, P = 0.025 < 0.05. The results showed that the efficacy of group A was better. There was a statistically significant difference in OS between the two groups (54:27, P = 0.002).

Conclusions: The results indicated that the treatment regimens containing daratumumab could prolong the OS of patients, suggesting that for MM patients with extramedullary disease(EMD), daratumumab-based combination treatment regimens can be given priority.

Variant acute promyelocytic leukemia (vAPL) represents a certain type of APL case whose specific fusion proteins, which are relevant but atypical variants, may fail to be identified by polymerase chain reaction (PCR) and fluorescence in situ hybridization (FISH) and requires identification through next-generation sequencing (NGS) or RNA sequencing (RNA-seq). These patients often show insensitivity to arsenic trioxide (ATO) or all trans-retinoic acid (ATRA) and therefore exhibit unclear prognosis. Venetoclax (VEN), an oral small-molecule B-cell lymphoma 2 (BCL-2) inhibitor, demonstrates effectiveness and safety as a cytoreduction therapy for pediatric APL and has shown some promising effect on relapsed or refractory APL. However, only a few cases have been reported on the treatment of vAPL with a single drug or multiple drugs combined with VEN. Therefore, this study reported the first vAPL case with the TFG-RARA fusion gene, who achieved complete remission (CR) with oral administration of VEN and ATRA, and remained CR till submission. Our study indicated that VEN may have a good therapeutic effect and contribute to a better prognosis of vAPL and warranted further application among APL patients.

Allogeneic bone marrow transplantation is a curative intervention for both neoplastic and non-malignant conditions. However, not all patients have an HLA-matched donor. Therefore, the development of an approach that expand the donor pool was of paramount relevance. The development of post-transplantation cyclophosphamide as graft versus host disease prophylaxis allows the safe use of haploidentical donors, solving the donor availability problem to the vast majority of patients in need. The present paper reviews the history of the development of haploidentical transplantation at Johns Hopkins University, from the bench to the bedside.

Objective: Acute myeloid leukemia (AML) stands out as a malignancy of the stem cell precursors of the myeloid lineage. Bone-marrow mesenchymal stem cell-derived exosomes (BMSC-exos) affect AML progression. We explored the effects and mechanism of BMSC-exos on AML cell proliferation and apoptosis.

Methods: Human AML cells (MOLM-16, MV-4-11) and normal human hematopoietic cells (GM12878) cultured in vitro were treated with exos extracted from BMSCs that transfected with microRNA (miR)-139-5p-mimics, ovβ-catenin, or miR-139-5p-inhibitor. BMSC morphology was observed by a microscopy, and its adipogenic and osteogenic differentiation abilities were assessed by oil red O staining and alizarin red S staining. BMSC-exos were extracted by ultracentrifugation, and their morphology was observed by a transmission electron microscopy. BMSC-exos were identified by nanoparticle tracking analysis and Western blot. The binding sites between miR-139-5p and β-catenin were predicted by TargetScan database, and then validated by dual-luciferase reporter assay. mRNA levels of miR-139-5p and β-catenin, cell proliferation, and apoptosis were evaluated by RT-qPCR, CCK-8, and flow cytometry. The expressions of CD63, CD81, TSG101, and GRP94 and the proteins of β-catenin, Bax, and Bcl-2 were determined by Western blot.

Results: miR-139-5p was poorly expressed in AML cell lines. miR-139-5p overexpression reduced AML cell viability/proliferation/Bcl-2 level, and raised apoptosis/Bax level. BMSC-exos repressed AML cell proliferation and promoted apoptosis via miR-139-5p. miR-139-5p targeted to inhibit β-catenin expression. Subsequently, up-regulated β-catenin partially counteracted the effects of miR-139-5p in BMSC-exos on AML cell proliferation and apoptosis.

Conclusion: BMSC-exos targeted to repress β-catenin expression by miR-139-5p, limited AML cell proliferation and facilitated apoptosis.

Purpose: The study aimed to access the impact of related factors on the long-term survival of patients with B-cell acute lymphoblastic leukemia (B-ALL) by analyzing clinical characteristics of B-ALL patients, and observed the significance of dynamic measurable residual disease (MRD) assessment for the prognosis and treatment selection of B-ALL patients, aiming to deepen the understanding of the disease and improve the survival prognosis of B-ALL patients.

Methods: The clinical characteristics of 65 patients with B-ALL were collected to calculate the median overall survival (OS) and median disease-free survival (PFS), and to evaluate the significance of survival analysis guided by dynamic MRD assessment.

Results: The survival analysis based on dynamic MRD assessment suggested that B-ALL patients who maintained MRD negative status during dynamic assessment after induction chemotherapy had better survival outcomes in the comparison of progression-free survival between subgroups, with statistically significant differences (P = 0.0002 (HR: 0.26, 95% CI: 0.13-0.51)). High-risk B-ALL patients who maintained negative MRD status during dynamic assessment after induction chemotherapy had longer median progression - free survival, and the survival difference between subgroups was statistically significant (P = 0.0016 (HR: 0.28, 95% CI: 0.09-0.48)).

Conclusion: Dynamic MRD assessment had significant clinical value: maintaining negative MRD status during dynamic assessment can improve the prognosis and survival of B-ALL patients; dynamic MRD assessment after induction chemotherapy can help guide subsequent treatment, which could provide reference for the advancement of future treatment strategies.

Background: Long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been identified in multiple myeloma (MM); its influence on the homing behavior in MM cells is unclear. This study elucidates the impact and mechanism by which MALAT1 affects the homing behavior in MM cells.

Methods: Bone marrow was obtained from patients with MM. MALAT1 and C-X-C motif chemokine receptor 4 (CXCR4) expression in cluster of differentiation 138-purified (CD138) plasma cells were detected by qRT-PCR and Western blotting. MALAT1, CXCR4, and C-X-C motif chemokine ligand 12 (CXCL12) influences on MM cell viability, proliferation, and invasion was monitored by CCK-8, 5-Ethynyl-2'-deoxyuridine, and Transwell assays. qRT-PCR, Western blotting, and ELISA were utilized to detect homing effect-related proteins in MM cells, including intercellular adhesion molecule 1 (ICAM-1) and very late antigen-4 (VLA-4).

Results: MALAT1 and CXCR4 were overexpressed in CD138-purified plasma cells from bone marrow of MM patients, associating with bone damage. MALAT1 upregulated CXCR4 in MM cells. MALAT1 overexpression enhanced MM cell viability, proliferation, and invasion, whereas CXCR4 silencing reversed them. CXCR4 silencing attenuated MALAT1 induction on ICAM-1 and VLA-4 expression in MM cells. CXCL12 upregulation intensified MM cell proliferation and invasion and ICAM-1 and VLA-4 expression in MM cells. MALAT1 silencing counteracted the impact of CXCL12.

Conclusion: MALAT1 silencing may repress CXCL12 induction on MM cell proliferation, invasion, and homing behavior by inhibiting CXCR4. MALAT1 may be a promising target for MM treatment.