Targeting MCL1-Driven Anti-apoptotic Pathways Overcomes Blast Progression After Hypomethylating Agent Failure in Chronic Myelomonocytic Leukemia

Authors

Guillermo Montalban-Bravo
Natthakan Thongon
Juan Jose Rodriguez-Sevilla
Feiyang Ma
Irene Ganan-Gomez
Hui Yang
Yi June Kim
Vera Adema
Bethany Wildeman
Tomoyuki Tanaka
Faezeh Darbaniyan
Gheath Al-Atrash
Karen Dwyer
Sanam Loghavi
Rashmi Kanagal-Shamanna
Xingzhi Song
Jianhua Zhang
Koichi Takahashi
Hagop Kantarjian
Guillermo Garcia-Manero
Simona Colla

Publication Date

6-18-2024

Journal

Cell Reports Medicine

Abstract

RAS pathway mutations, which are present in 30% of patients with chronic myelomonocytic leukemia (CMML) at diagnosis, confer a high risk of resistance to and progression after hypomethylating agent (HMA) therapy, the current standard of care for the disease. Here, using single-cell, multi-omics technologies, we seek to dissect the biological mechanisms underlying the initiation and progression of RAS pathway-mutated CMML. We identify that RAS pathway mutations induce transcriptional reprogramming of hematopoietic stem and progenitor cells (HSPCs) and downstream monocytic populations in response to cell-intrinsic and -extrinsic inflammatory signaling that also impair the functions of immune cells. HSPCs expand at disease progression after therapy with HMA or the BCL2 inhibitor venetoclax and rely on the NF-κB pathway effector MCL1 to maintain survival. Our study has implications for the development of therapies to improve the survival of patients with RAS pathway-mutated CMML.

Keywords

Leukemia, Myelomonocytic, Chronic, Myeloid Cell Leukemia Sequence 1 Protein, Humans, Apoptosis, Animals, Mutation, Mice, Signal Transduction, Hematopoietic Stem Cells, Disease Progression, Sulfonamides, NF-kappa B, DNA Methylation, Bridged Bicyclo Compounds, Heterocyclic, Blast Crisis

Comments

Supplementary Materials

PMID: 38781960