# Screening for Antileukemia Agents in FMS-like Tyrosine Kinase 3 (FLT3)-Mutated Acute Myeloid Leukemia Cells

## TL;DR

This study identifies a compound, HI042, that shows promise in treating a high-risk type of leukemia caused by a specific genetic mutation.

## Contribution

HI042 is a newly identified compound that induces differentiation and apoptosis in FLT3-ITD-mutated AML cells and synergizes with existing therapies.

## Key findings

- HI042 selectively reduces viability and induces apoptosis in FLT3-ITD-positive AML cells.
- HI042 increases differentiation markers and synergizes with quizartinib to enhance antileukemic effects.
- HI042 shows structural similarity to retinoic acid analogues and induces differentiation in MOLM-13 cells.

## Abstract

Acute myeloid leukemia (AML) remains a challenging hematological
malignancy due to its genetic heterogeneity, high relapse rates, and
limited therapeutic options for refractory cases. FMS-like tyrosine
kinase 3 (FLT3)-internal tandem duplication (FLT3-ITD) mutations are
among the most frequent genetic alterations in AML, associated with
poor prognosis and treatment resistance. In this study, we investigated
the antileukemic potential of compound HI042, identified from a library
of 78 molecules, focusing on its effects on FLT3-ITD-mutated AML models.
HI042 selectively reduced the viability of FLT3-ITD-positive cell
lines, induced apoptosis, disrupted cell cycle progression, and diminished
the clonogenic potential. Chemoinformatics analysis revealed structural
similarities between HI042 and retinoic acid analogues, known for
their differentiation-inducing effects. Consistently, HI042 treatments
increased the level of differentiation markers, including CD11b and
transcription factors such as PU.1 and C/EBPs, particularly in MOLM-13
cells. Furthermore, combining HI042 with the FLT3 inhibitor quizartinib
synergistically enhanced apoptosis and reduced cell proliferation.
These findings highlight HI042’s dual activity in inducing
differentiation and apoptosis while synergizing with established therapies.
Overall, HI042 emerges as a promising candidate for targeted therapies
against FLT3-ITD-mutated AML, addressing a critical need for novel
treatment strategies for this high-risk AML subgroup.