Background: Acute myeloid leukemia (AML) is a hematopoietic malignancy with a prognosis that varies with genetic heterogeneity of hematopoietic stem/progenitor cells (HSPCs). Induction chemotherapy with cytarabine and anthracycline has been the standard care for newly diagnosed AML, but about 30% of patients have no response to this regimen. The resistance mechanisms require deeper understanding.Methods: In our study, using single-cell RNA sequencing, we analyzed the heterogeneity of bone marrow CD34 + cells from newly diagnosed patients with AML who were then divided into sensitive and resistant groups according to their responses to induction chemotherapy with cytarabine and anthracycline. We verified our findings by TCGA database, GEO datasets, and multiparameter flow cytometry.
Results:We established a landscape for AML CD34 + cells and identified HSPC types based on the lineage signature genes. Interestingly, we found a cell population with CRIP1 high LGALS1 high S100As high showing features of granulocyte-monocyte progenitors was associated with poor prognosis of AML. And two cell populations marked by CD34 + CD52 + or CD34 + CD74 + DAP12 + were related to good response to induction therapy, showing characteristics of hematopoietic stem cells.
Conclusion:Our study indicates the subclones of CD34 + cells confers for outcomes of AML and provides biomarkers to predict the response of patients with AML to induction chemotherapy.
BackgroundChemoresistance is emerging as a major barrier to successful treatment in acute myeloid leukemia (AML), and bone marrow stromal cells (BMSCs) protect leukemia cells from chemotherapy eventually leading to recurrence. This study was designed to investigate the role of p21-activated kinase 1 (PAK1) in AML progression and chemosensitivity, highlighting the mechanism of stroma-mediated chemoresistance.MethodsThe GEPIA and TCGA datasets were used to analyze the relationship between PAK1 mRNA expression and various clinical parameters of AML patients. Cell proliferation and apoptosis were examined to evaluate the role of PAK1 on chemosensitivity in AML by silencing PAK1 with shRNA or small molecular inhibitor. Human BMSC (HS-5) was utilized to mimic the leukemia bone marrow microenvironment (BMM) in vitro, and co-culture model was established to investigate the role of PAK1 in BMSC-mediated drug resistance.Resultsp21-activated kinase 1 high expression was shown to be associated with shorter overall survival in AML patients. The silence of PAK1 could repress cell proliferation, promote apoptosis, and enhance the sensitivity of AML cells to chemotherapeutic agents. More importantly, BMSCs induced PAK1 up-regulation in AML cells, subsequently activating the ERK1/2 signaling pathway. The effect of BMSC-mediated apoptotic-resistance could be partly reversed by knock down of PAK1.Conclusionp21-activated kinase 1 is a potential prognostic predictor for AML patients. PAK1 may play a pivotal role in mediating BMM-induced drug resistance, representing a novel therapeutic target in AML.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignant blood disorder with a high rate of relapse. Patients relapse as a result of minimal residual disease (MRD), which originates from residual T-ALL cells in the bone marrow microenvironment (BMM). In the present study, it is observed that adipocytes increase dramatically in the BMM of T-ALL patients after exposure to chemotherapeutic drugs. Then, it is proved that adipocytes attract T-ALL cells by releasing CXCL13 and support leukemia cell survival by activating the Notch1 signaling pathway via DLL1 and Notch1 binding. Furthermore, it is verified that dexamethasone (DEX) induces adipogenic differentiation by enhancing the expression of SREBF1 in bone marrow mesenchymal stromal cells (BMSCs), and an SREBF1 inhibitor significantly decreases the adipogenic potential of BMSCs and the subsequent ability of adipocytes to support T-ALL cells in vitro and in vivo. These findings confirm that the differentiation of BMSCs to adipocytes induced by DEX contributes to MRD in T-ALL and provides an auxiliary clinical treatment to reduce the recurrence rate.
T‐Cell Acute Lym‐phoblastic Leukemia
In article number 2205854, Jingjing Ye, Min Ji, Chunyan Ji, and co‐workers observed aberrant adipogenesis in the bone marrow of chemotherapy‐treated T‐cell acute lymphoblastic leukemia (T‐ALL) patients, and the differentiated‐adipocytes attract and support residual T‐ALL cells. Last, an SREBF1 inhibitor demonstrates superior improvement on therapeutic effect of dexamethason by reducing adipogenesis and provides a feasible strategy to solve the dilemma of recurrence.
BackgroundAcute myeloid leukemia (AML) is a fatal hematopoietic malignancy which has a prognosis that varies with genetic heterogeneity of its hematopoietic stem/progenitor cells(HSCPs). Intensive induction chemotherapy with cytarabine and anthracycline has been the standard of care for newly diagnosed AML, but about 30% of patients have no response to this regimen. The resistance mechanisms require deeper understanding. Methods In our study, using 10× Genomics, a high-throughput single cell RNA sequencing (scRNA-seq) platform, we analyzed the cellular heterogeneity of bone marrow CD34+ cells from newly diagnosed AML patients who were then divided into sensitive and resistant groups according to their responses to induction chemotherapy with cytarabine and anthracycline. ScRNA-seq data for healthy controls were obtained from the GEO database. We verified our findings by the TCGA database, GEO datasets and the multiparameter flow cytometry.ResultsFrom the integrative analysis of 60,402 cells, we established a landscape for single-cell CD34+ cells in AML patients and identified the hematopoietic stem/progenitor cell types based on the lineage signature genes. Interestingly, through recognizing the malignant-like clusters and comparing “resistant group” with “sensitive group”, we found a cell population with specific gene signatures (CRIP1highLGALS1highS100Ashigh) showing features of granulocyte-monocyte progenitors (GMP) was associated with poor prognosis of AML. And two cell populations of AML CD34+ cells marked by CD52+ or CD74+DAP12+ were related to good response of patients to induction therapy, showing characteristics of hematopoietic stem cell (HSC). ConclusionOur study indicates the heterogeneity of AML CD34+ cells confers for outcomes of AML and provides possible biomarkers to predict the response of AML patients to induction chemotherapy.
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