MPO and Trh within Leukemia Stem Cells Increased Chemosensitivity in Acute Myeloid Leukemia: A Single-Cell RNA Sequencing Approach

髓系白血病 造血 白血病 干细胞 医学 骨髓 内科学 髓样 癌症研究 肿瘤科 诱导化疗 养生 化疗 免疫学 生物 遗传学
作者
Chieh‐Lin Jerry Teng,Chung‐Hsing Chen,Tzu-Hung Hsiao,Tzu‐Chin Wu,Yu-Min Liao
出处
期刊:Blood [Elsevier BV]
卷期号:142 (Supplement 1): 4323-4323
标识
DOI:10.1182/blood-2023-174175
摘要

Introduction The “7+3” regimen is widely recognized as the established standard induction therapy for newly diagnosed acute myeloid leukemia (AML), exhibiting a complete remission (CR) rate of 70%. However, the prognosis for patients who do not achieve CR following induction remains discouraging. Leukemia stem cells (LSCs) are recognized as major contributors to chemoresistance in AML. Hence, it is crucial to identify potential targets within LSCs that can overcome chemoresistance. Patients and methods This prospective study involved 20 consecutive de novo AML patients who underwent “7+3” induction therapy. These patients were divided into CR (n=15) and non-CR (n=5) groups. By employing single-cell RNA sequencing (scRNA-seq), we meticulously examined the cellular states of bone marrow mononuclear cells from AML patients at the time of diagnosis and identified LSCs among these cells. The genetic profiles of the LSCs were subsequently compared between the CR and non-CR groups and further validated using independent cohorts. Results The non-CR AML patients exhibited a significant increase in the proportion of immature cells during hematopoiesis within the AML cell populations. Moreover, we found that expressions of MPO and TRH within LSCs were significantly higher in the CR than non-CR groups, which were further validated by independent cohorts. Furthermore, patients with higher expression of TRH and MPO demonstrated substantially improved relapse-free survival (p = 0.009 for TRH; p = 0.002 for MPO) and overall survival (p < 0.001 for TRH; p = 0.002 for MPO). The dysregulation of the OXPHOS pathway, along with altered interferon alpha and gamma responses, disrupted cholesterol homeostasis, and aberrant MYC activity, may contribute as underlying mechanisms for the observed association between MPO or TRH and chemotherapy response. Conclusions MPO and TRH in LSCs may increase chemosensitivity in AML and serve as chemoresponse biomarkers, offering potential benefits in guiding induction strategies for newly diagnosed AML patients
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