Targeting MCL1-driven anti-apoptotic pathways overcomes blast progression after hypomethylating agent failure in chronic myelomonocytic leukemia

  • Cell Rep Med. 2024 May 15:101585. doi: 10.1016/j.xcrm.2024.101585.
Guillermo Montalban-Bravo  1 ,  Natthakan Thongon  1 ,  Juan Jose Rodriguez-Sevilla  1 ,  Feiyang Ma  2 ,  Irene Ganan-Gomez  1 ,  Hui Yang  1 ,  Yi June Kim  1 ,  Vera Adema  1 ,  Bethany Wildeman  1 ,  Tomoyuki Tanaka  1 ,  Faezeh Darbaniyan  3 ,  Gheath Al-Atrash  4 ,  Karen Dwyer  4 ,  Sanam Loghavi  5 ,  Rashmi Kanagal-Shamanna  5 ,  Xingzhi Song  6 ,  Jianhua Zhang  6 ,  Koichi Takahashi  1 ,  Hagop Kantarjian  1 ,  Guillermo Garcia-Manero  1 ,  Simona Colla  7
Affiliations
  • 1. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 2. Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA.
  • 3. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 4. Department of Stem Cell Transplantation and Hematopoietic Biology and Malignancy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 5. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 6. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 7. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: [email protected].
PMID: 38781960 DOI: 10.1016/j.xcrm.2024.101585
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
CMML; MCL1; NF-kB; RAS; multiomics; progression; transcriptomics.
Products