{"title":"Gene Expression Profiling in Acute Myeloid Leukemia Patient Subgroups With High and Low Sensitivity Toward SYK Inhibitors","authors":"Marte Karen Brattås, Franziska Görtler, Silje Johansen, Kristin Paulsen Rye, Kimberley Joanne Hatfield, Håkon Reikvam","doi":"10.1002/hon.70058","DOIUrl":null,"url":null,"abstract":"<div>\n \n <p>Acute myeloid leukemia (AML) is a heterogeneous malignancy characterized by the uncontrolled proliferation of myeloid cells, and despite recent treatment advances, patient outcomes remain suboptimal. The cytoplasmic spleen tyrosine kinase (SYK) has emerged as a promising therapeutic target in AML due to its role in promoting leukemic cell survival, proliferation, and chemoresistance. This study investigates in vitro antiproliferative effects of SYK inhibitors on leukemia cells by analyzing 48 primary AML samples treated with five SYK inhibitors: fostamatinib, entospletinib, cerdulatinib, TAK-659, and RO9021. Our findings revealed significant heterogeneity among patients, leading to the identification of two distinct patient sample groups that were identified as having either high or low sensitivity toward SYK inhibitors. Furthermore, gene expression profiling through RNA sequencing of AML patient samples uncovered 97 significantly differentially expressed genes (DEGs) between the two patient groups with high or low in vitro sensitivity toward SYK inhibitors. Pathway enrichment analyses revealed that the high-sensitivity group was enriched in biological processes related to positive gene regulation and significant pathways included cell adhesion molecules and proteoglycans. In contrast, the low-sensitivity group showed enrichment in pathways related to PI3K-Akt signaling and JAK-STAT signaling.</p>\n <p>Gene set enrichment analysis further highlighted that high-sensitivity patient samples were upregulated in pathways associated with oxidative phosphorylation and MYC targets, whereas low-sensitivity patient samples showed enrichment in TGF beta signaling and IL6 JAK STAT3 signaling. These results identify gene expression profile signatures that may predict sensitivity to SYK inhibition and underscore the potential for personalized therapeutic strategies in AML.</p>\n </div>","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 2","pages":""},"PeriodicalIF":3.3000,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Hematological Oncology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/hon.70058","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Acute myeloid leukemia (AML) is a heterogeneous malignancy characterized by the uncontrolled proliferation of myeloid cells, and despite recent treatment advances, patient outcomes remain suboptimal. The cytoplasmic spleen tyrosine kinase (SYK) has emerged as a promising therapeutic target in AML due to its role in promoting leukemic cell survival, proliferation, and chemoresistance. This study investigates in vitro antiproliferative effects of SYK inhibitors on leukemia cells by analyzing 48 primary AML samples treated with five SYK inhibitors: fostamatinib, entospletinib, cerdulatinib, TAK-659, and RO9021. Our findings revealed significant heterogeneity among patients, leading to the identification of two distinct patient sample groups that were identified as having either high or low sensitivity toward SYK inhibitors. Furthermore, gene expression profiling through RNA sequencing of AML patient samples uncovered 97 significantly differentially expressed genes (DEGs) between the two patient groups with high or low in vitro sensitivity toward SYK inhibitors. Pathway enrichment analyses revealed that the high-sensitivity group was enriched in biological processes related to positive gene regulation and significant pathways included cell adhesion molecules and proteoglycans. In contrast, the low-sensitivity group showed enrichment in pathways related to PI3K-Akt signaling and JAK-STAT signaling.
Gene set enrichment analysis further highlighted that high-sensitivity patient samples were upregulated in pathways associated with oxidative phosphorylation and MYC targets, whereas low-sensitivity patient samples showed enrichment in TGF beta signaling and IL6 JAK STAT3 signaling. These results identify gene expression profile signatures that may predict sensitivity to SYK inhibition and underscore the potential for personalized therapeutic strategies in AML.
期刊介绍:
Hematological Oncology considers for publication articles dealing with experimental and clinical aspects of neoplastic diseases of the hemopoietic and lymphoid systems and relevant related matters. Translational studies applying basic science to clinical issues are particularly welcomed. Manuscripts dealing with the following areas are encouraged:
-Clinical practice and management of hematological neoplasia, including: acute and chronic leukemias, malignant lymphomas, myeloproliferative disorders
-Diagnostic investigations, including imaging and laboratory assays
-Epidemiology, pathology and pathobiology of hematological neoplasia of hematological diseases
-Therapeutic issues including Phase 1, 2 or 3 trials as well as allogeneic and autologous stem cell transplantation studies
-Aspects of the cell biology, molecular biology, molecular genetics and cytogenetics of normal or diseased hematopoeisis and lymphopoiesis, including stem cells and cytokines and other regulatory systems.
Concise, topical review material is welcomed, especially if it makes new concepts and ideas accessible to a wider community. Proposals for review material may be discussed with the Editor-in-Chief. Collections of case material and case reports will be considered only if they have broader scientific or clinical relevance.