Targeting RNA modification and mitochondrial metabolism cross talk in leukemic stem cells with CDK7 inhibitor TGN-1062
Treatment refractoriness and relapse in acute myeloid leukemia (AML) are driven by leukemia stem cells (LSCs), 1 which depend on mitochondrial fusion to support fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS), metabolic processes that sustain their bioenergetic needs. 2,3The cyclindependent kinase 7 (CDK7), crucial for cell cycle control and transcriptional regulation, is overexpressed in hematopoietic stem/progenitor cells of AML patients and linked to poor outcomes. 4,5harmacological inhibition of CDK7 reduced the LSC growth and prolonged survival in a mouse model of chronic myeloid leukemia, 6 underscoring the potential role of CDK7 in LSC homeostasis and activity.We have designed TGN-1062 (TGN), a novel, potent and reversible CDK7 inhibitor which binds to the catalytic pocket of CDK7 (supplemental Figure 1; supplemental Methods). [7][8]8][9] Herein, we present the first report on how TGN targets the cross talk between RNA modification and mitochondrial metabolism to AML LSCs.
Authors
- Alexis Weston
- Dinh Hoa Hoang
- Mohan R. Kaadige (ORCID: https://orcid.org/0000-0003-3813-9107)
- Ya‐Huei Kuo (ORCID: https://orcid.org/0000-0003-2595-0419)
- Le Xuan Truong Nguyen (ORCID: https://orcid.org/0000-0001-5464-0861)
- Guido Marcucci
- Zhuo Li (ORCID: https://orcid.org/0000-0001-8774-0471)
- Lucy Ghoda (ORCID: https://orcid.org/0000-0002-8212-3586)
- Trason Thode (ORCID: https://orcid.org/0000-0002-4307-1234)
- Lokesh Nigam (ORCID: https://orcid.org/0000-0003-2350-9910)
- Patrick Pirrotte (ORCID: https://orcid.org/0000-0003-1360-6039)
- Melissa Valerio (ORCID: https://orcid.org/0000-0001-7897-2932)
- Yuriy Shostak (ORCID: https://orcid.org/0000-0003-2891-7905)
- Khyatiben V. Pathak (ORCID: https://orcid.org/0000-0002-8050-0747)
- Wei Li (ORCID: https://orcid.org/0000-0001-7864-404X)
- Bin Zhang (ORCID: https://orcid.org/0000-0002-4371-4746)
- Jianjun Chen (ORCID: https://orcid.org/0000-0003-3749-2902)
- HyunJun Kang
- Leying Zhang (ORCID: https://orcid.org/0000-0002-5285-0088)
- Brooke Lovell (ORCID: https://orcid.org/0009-0008-1023-2186)
- Sunil Sharma
- Nathaniel Hansen
Institutions
- Translational Genomics Research Institute (US)
- City Of Hope National Medical Center (US)
- City of Hope (US)
- Beckman Research Institute
Publication Details
- Journal
- Blood Advances
- Published
- 2025-02-05
- DOI
- https://doi.org/10.1182/bloodadvances.2024014225
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Comprehensive Cancer Center, City of Hope
- National Institutes of Health
- National Cancer Institute