SR-B1 deficiency suppresses progression in acute myeloid leukemia via ferroptosis and reverses resistance to venetoclax.

in Free radical biology & medicine by Junfeng Shi, Yifeng Cheng, Lixue Wang, Wen Xing, Yudi Li, Xiulin Sun, Yunpeng Lv, Yichuan Zhang, Yanming Li, Wenhua Zhao

TLDR

  • The study found that SR-B1 is a critical regulator of AML cell proliferation and a potential therapeutic target against AML
  • BLT-1 treatment can reverse drug-resistance of venetoclax and promote AML cell death via ferroptosis
  • The study provides new insights into the regulatory mechanism of SR-B1 in AML and suggests a potential therapeutic strategy for AML treatment

Abstract

Increase of immature myeloid cells in the bone marrow drives the development of acute myeloid leukemia (AML). The study aimed to clarify the biological function and regulatory mechanism of scavenger receptor class B type 1 (SR-B1) in AML, mainly its effect on ferroptosis and the influences on leukemogenesis and resistance to venetoclax. In this study, we found that the SR-B1 deficiency directly reduced the invasion and promoted death of malignant cells in AML. Strikingly, SR-B1 deficiency could up-regulated the expression of ferroptosis-related proteins to facilitate the occurrence of ferroptosis in vivo, and could also down-regulated the expression of apoptosis related protein B-cell lymphoma-2 (BCL-2). And then, we confirmed SR-B1 inhibitor block lipid transport-1 (BLT-1) had a superior efficacy in AML cells and AML model mice. The study found that whether SR-B1 deficiency or BLT-1 treatment could cause iron deposition and the accumulation of lipid peroxides in vivo, thereby suppressing leukemogenesis through ferroptosis. Critically, we found that SR-B1 inhibitor BLT-1 can reverse drug-resistance of venetoclax to promote AML cells death via ferroptosis. Our finding identified that SR-B1 as a critical regulator of the proliferation in AML which can provide a promising therapeutic strategy against malignant myeloid leukemia cells and drug-resistance.

Overview

  • The study examined the biological function and regulatory mechanism of scavenger receptor class B type 1 (SR-B1) in acute myeloid leukemia (AML)
  • The study aimed to clarify the role of SR-B1 in ferroptosis and its influence on leukemogenesis and resistance to venetoclax
  • The study identified SR-B1 as a critical regulator of AML cell proliferation and provided a promising therapeutic strategy against malignant myeloid leukemia cells and drug-resistant cells

Comparative Analysis & Findings

  • SR-B1 deficiency directly reduced the invasion and promoted death of malignant cells in AML
  • SR-B1 deficiency up-regulated the expression of ferroptosis-related proteins to facilitate the occurrence of ferroptosis in vivo
  • BLT-1 treatment had a superior efficacy in AML cells and AML model mice and could reverse drug-resistance of venetoclax to promote AML cell death via ferroptosis

Implications and Future Directions

  • The study provides new insights into the regulatory mechanism of SR-B1 in AML and suggests a potential therapeutic target for the treatment of AML
  • Future studies should investigate the feasibility and optimal dosing of BLT-1 for clinical application
  • The study paves the way for further research on the use of SR-B1 inhibitors as a combination therapy for AML treatment
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