2. Academic Validation
  3. Targeting MCL1-driven anti-apoptotic pathways overcomes blast progression after hypomethylating agent failure in chronic myelomonocytic leukemia

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

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: scolla@mdanderson.org.
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.

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