Targeting the Super Elongation Complex to Prevent Hematopoietic Stem Cell Expansion and Blood Cancer Risk

Background

It is estimated that over 1.7 million people in the United States are living with or in remission from blood cancers such as leukemias, lymphomas, myeloma, and myeloproliferative neoplasms (MPNs), and approximately 192,070 new cases were expected in 2025. Though these cancers are common, their heritable components are poorly understood, limiting the creation of effective treatments. By uncovering new risk factors and pathways, more effective and efficient agents can be utilized to target, treat, or prevent these diseases.

Technology Overview

To combat this lack of knowledge, Boston Children’s Hospital researchers focused on identifying additional inherited risk factors for blood cancers and understanding the abnormal pathways that lead to these diseases. The group found that variants in the CTR9 gene, which codes for a subunit of the PAF1 transcription elongation complex, significantly increase the risk of MPNs by tenfold. This elevated risk results from the variants causing increased expression and activity of the super elongation complex (SEC). Inhibiting the SEC can reduce excessive hematopoietic stem cell (HSC) self-renewal in both CTR9-mediated and non-mediated ways, presenting a novel approach to treat blood cancers. The suppression of HSC expansion is observed even in the absence of CTR9 perturbation, suggesting a general strategy for preventing HSC expansion and reducing the risk of blood cancers. Inhibiting SEC components like MLLT3/AF9 or CDK9 can effectively prevent HSC expansion hence heritable blood cancers, including the ones driven by CTR9 mutations, providing a promising approach for new therapies.

Applications

• Treatment of predisposed individuals to reduce their risk of blood cancers;
• Targeted treatment of blood cancers.

Advantages

• This approach limits the risk of developing blood cancers in predisposed individuals, hence preventing the initiation of myeloid malignancies.
• It is a promising approach for targeted therapies, potentially improving treatment outcomes and reducing the significant organ toxicity associated with current options such as chemotherapy.

Publications

Zhao, J., Cato, L. D., Arora, U. P., Bao, E. L., Bryant, S. C., Williams, N., Jia, Y., Goldman, S. R., Nangalia, J., Erb, M. A., Vos, S. M., Armstrong, S. A., & Sankaran, V. G. (2024). Inherited blood cancer predisposition through altered transcription elongation. Cell, 187(3), 642–658.e19. https://doi.org/10.1016/j.cell.2023.12.016