WITHDRAWN: A Druggable Tumor Suppressor and Leukemic Stem Cell Marker

Area of Science:

• Hematology
• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Acute myeloid leukemia (AML) frequently relapses due to chemotherapy-resistant leukemic stem cells (LSCs).
• Relapsed AML has a poor prognosis and is unresponsive to current therapies.
• Identifying novel therapeutic targets for AML is crucial.

Purpose of the Study:

• To nominate druggable therapeutic targets for AML using a large-language model (LLM) agent.
• To investigate the role of Angiotensin II Receptor Type 2 (AGTR2/AT2R) in AML pathogenesis and LSC function.
• To evaluate the therapeutic potential of an AT2R agonist in AML models.

Main Methods:

• Developed an LLM agent integrating multi-modal data to identify therapeutic targets.
• Functional studies on 68 primary human AML samples and 21 patient-derived xenograft (PDX) models.
• Analysis of AT2R expression, chromatin rearrangements, and epigenetic silencing of AGTR2.
• Murine AML models with Agtr2 knockdown or enforced expression.
• Treatment of AML PDX models with buloxibutid (C21), an AT2R agonist.

Main Results:

• Higher AGTR2 (AT2R) expression correlated with better chemotherapy response and survival in AML.
• Leukemic stem cells (LSCs) consistently lacked AT2R expression and were enriched after chemotherapy.
• Epigenetic silencing, not mutation, was identified as the mechanism for AT2R downregulation in AML.
• Enforced AT2R expression in murine models delayed AML progression, reduced LSC frequency, and suppressed stemness.
• Buloxibutid (C21) significantly inhibited AML progression and enhanced chemotherapy efficacy, especially in relapsed AML.

Conclusions:

• AT2R absence is a marker for LSCs, and AT2R functions as a tumor suppressor in AML.
• Epigenetic silencing of AGTR2 contributes to AT2R downregulation and AML relapse.
• Targeting AT2R with agonists like buloxibutid (C21) represents a promising therapeutic strategy for AML, particularly relapsed cases.