Lenalidomide-induced pure red cell aplasia: clinical characteristics and mechanistic analysis
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PROVIDER: PRJNA1021157 | ENA |
REPOSITORIES: ENA
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Project description:The RVd therapy, combining lenalidomide, bortezomib, and dexamethasone, is a mainstay treatment for multiple myeloma, typically eliciting immune activation and myeloma cell clearance, alleviating anemia and associated symptoms. In a unique multiple myeloma case, the patient developed pure red cell aplasia (PRCA) following RVd treatment, despite the absence of common PRCA triggers. In vitro analyses revealed severe erythropoiesis impairment in this patient, with lenalidomide emerging as a pivotal disruptor of erythroid development, potentially driving PRCA. Single-cell transcriptome analysis unveiled a notable increase in hyperactive cluster of differentiation (CD)8+ T cells in the patient's bone marrow. The few remaining erythroid progenitors in the patient's bone marrow exhibited developmental dysfunction and immune-related pathway activation. Unexpectedly, these erythroid cells displayed abnormally high expression of major histocompatibility class I (MHCI). Functional assays demonstrated that the addition of lenalidomide further augmented MHCI expression in the patient's erythroid progenitors. Drug-induced increases in antigen presentation by immune erythrocytes emerged as the potential driving force behind hyperactive T cell attacks and subsequent development of PRCA. This study not only elucidates the mechanism underlying lenalidomide-induced PRCA in this rare case, but also underscore the importance of considering the MHCI gene in erythroid cells during clinical trials and drug administration.
2025-02-28 | GSE244044 | GEO
Project description:The RVd therapy, combining lenalidomide, bortezomib, and dexamethasone, is a mainstay treatment for multiple myeloma, typically eliciting immune activation and myeloma cell clearance, alleviating anemia and associated symptoms. In a unique multiple myeloma case, the patient developed pure red cell aplasia (PRCA) following RVd treatment, despite the absence of common PRCA triggers. In vitro analyses revealed severe erythropoiesis impairment in this patient, with lenalidomide emerging as a pivotal disruptor of erythroid development, potentially driving PRCA. Single-cell transcriptome analysis unveiled a notable increase in hyperactive cluster of differentiation (CD)8+ T cells in the patient's bone marrow. The few remaining erythroid progenitors in the patient's bone marrow exhibited developmental dysfunction and immune-related pathway activation. Unexpectedly, these erythroid cells displayed abnormally high expression of major histocompatibility class I (MHCI). Functional assays demonstrated that the addition of lenalidomide further augmented MHCI expression in the patient's erythroid progenitors. Drug-induced increases in antigen presentation by immune erythrocytes emerged as the potential driving force behind hyperactive T cell attacks and subsequent development of PRCA. This study not only elucidates the mechanism underlying lenalidomide-induced PRCA in this rare case, but also underscore the importance of considering the MHCI gene in erythroid cells during clinical trials and drug administration.
2025-02-28 | GSE244043 | GEO
Project description:Lenalidomide-induced pure red cell aplasia: clinical characteristics and mechanistic analysis [scRNA-seq]
| PRJNA1021160 | ENA
Project description:Lenalidomide-induced pure red cell aplasia: clinical characteristics and mechanistic analysis [bulkRNA-seq]
| PRJNA1021159 | ENA
Project description:The RVd therapy, combining lenalidomide, bortezomib, and dexamethasone, is a mainstay treatment for multiple myeloma. A multiple myeloma patient developed pure red cell aplasia (PRCA) following RVd treatment, despite the absence of common PRCA triggers. In vitro analyses revealed lenalidomide as a pivotal disruptor of erythropoiesis. Single-cell transcriptome analysis unveiled hyperactive CD8+ T cells and impaired erythropoiesis in the patient's bone marrow. Unexpectedly, the patient's erythroid cells displayed abnormally high expression of genes in the antigen presentation pathway, particularly those for major histocompatibility class I (MHC-I) molecules. Functional assays demonstrated that lenalidomide treatment further augmented MHC-I expression in the patient's erythroid cells. Blocking MHC-I or depleting T cells alleviate the defective erythropoiesis of PRCA, suggesting that the interaction between erythroid cells with elevated MHC-I and T cells in the bone marrow might contribute to PRCA. Taken together, our study revealed a novel mechanism underlying lenalidomide-induced PRCA in treating cancer patients.
2024-09-03 | PXD055495 |
Project description:This SuperSeries is composed of the SubSeries listed below.
2025-02-28 | GSE244045 | GEO
Project description:Pure red cell aplasia (PRCA) is a rare disorder characterized by marked erythroid hypoplasia with maturation arrest in the bone marrow. Secondary acquired PRCA may be associated with hematologic disorders. A few case reports have described PRCA associated with multiple myeloma (MM). However, the clinical course and mechanism of PRCA associated with MM remain unknown. We herein report two cases of PRCA associated with MM in patients undergoing treatment with lenalidomide.
| S-EPMC6037886 | biostudies-other
Project description:Pure red cell aplasia is an orphan disease, and as such lacks rationally established standard therapies. Most cases are idiopathic; a subset is antibody-mediated. There is overlap between idiopathic cases and those with T-cell large granular lymphocytic leukemia, hypogammaglobulinemia, and low-grade lymphomas. In each of the aforementioned, the pathogenetic mechanisms may involve autoreactive cytotoxic responses. We selected 62 uniformly diagnosed pure red cell aplasia patients and analyzed their pathophysiologic features and responsiveness to rationally applied first-line and salvage therapies in order to propose diagnostic and therapeutic algorithms that may be helpful in guiding the management of prospective patients, 52% of whom were idiopathic, while the others involved large granular lymphocytic leukemia, thymoma, and B-cell dyscrasia. T-cell-mediated responses ranged between a continuum from polyclonal to monoclonal (as seen in large granular lymphocytic leukemia). During a median observation period of 40 months, patients received a median of two different therapies to achieve remission. Frequently used therapy included calcineurin-inhibitors with a steroid taper yielding a first-line overall response rate of 76% (53/70). Oral cyclophosphamide showed activity, albeit lower than that produced by cyclosporine. Intravenous immunoglobulins were effective both in parvovirus patients and in hypogammaglobulinemia cases. In salvage settings, alemtuzumab is active, particularly in large granular lymphocytic leukemia-associated cases. Other potentially useful salvage options include rituximab, anti-thymocyte globulin and bortezomib. The workup of acquired pure red cell aplasia should include investigations of common pathological associations. Most effective therapies are directed against T-cell-mediated immunity, and therapeutic choices need to account for associated conditions that may help in choosing alternative salvage agents, such as intravenous immunoglobulin, alemtuzumab and bortezomib.
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Project description:Idiopathic pure red cell aplasia (PRCA) and secondary PRCA associated with thymoma and large granular lymphocyte leukemia are generally considered to be immune-mediated. The PRCA2004/2006 study showed that poor responses to immunosuppression and anemia relapse were associated with death. PRCA may represent the prodrome to MDS. Thus, clonal hematopoiesis may be responsible for treatment failure. We investigated gene mutations in myeloid neoplasm-associated genes in acquired PRCA. We identified 21 mutations affecting amino acid sequences in 11 of the 38 adult PRCA patients (28.9%) using stringent filtering of the error-prone sequences and SNPs. Four PRCA patients showed 7 driver mutations in TET2, DNMT3A and KDM6A, and 2 PRCA patients carried multiple mutations in TET2. Five PRCA patients had mutations with high VAFs exceeding 0.3. These results suggest that clonal hematopoiesis by stem/progenitor cells might be related to the pathophysiology of chronic PRCA in certain adult patients.
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Project description:Pure red cell aplasia (PRCA) is a rare disorder characterized by inhibition of erythroid precursors in the bone marrow and normochromic, normocytic anaemia with reticulocytopenia. Among 51 PRCA patients, we identified 12 (24%) patients having monoclonal gammopathy, monoclonal gammopathy of undetermined significance or smouldering multiple myeloma, with presence of monoclonal protein or abnormal serum free light chains and atypical bone marrow features of clonal plasmacytosis, hypercellularity and fibrosis. Thus far, three patients treated with anti-myeloma based therapeutics have responded with reticulocyte recovery and clinical transfusion independence, suggesting plasma cells play a key role in the pathogenesis of this specific monoclonal gammopathy-associated PRCA.
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