A CADASIL NOTCH3 mutation leads to clonal hematopoiesis and expansion of Dnmt3a-R878H hematopoietic clones

Sánchez-Lanzas, R; Barclay, J; Chardas, A; Kalampalika, F; Jiménez-Pompa, A; Gallipoli, P; Ganuza, M

Abstract

Clonal hematopoiesis (CH) is nearly universal in the elderly. The molecular and cellular mechanisms driving CH and the clinical consequences of carrying clonally derived mutant mature blood cells are poorly understood. We recently identified a C223Y mutation in the extracellular domain (ECD) of NOTCH3 as a putative CH driver in mice. Provocatively, germline NOTCH3 ECD mutations perturbing cysteine numbers cause Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), a type of vascular dementia, suggesting an unexpected link between CADASIL and CH. Here, we formally demonstrated that mouse hematopoietic stem and progenitor cells (HSPCs) expressing CADASIL-related NOTCH3(C455R) exhibit a proliferative advantage resulting in robust cellular expansion in vivo and in vitro. Co-expression of NOTCH3(C455R) and Dnmt3a(R878H), homologous to a frequent human CH mutation, increased the fitness of NOTCH3(C455R) HSPCs, demonstrating their functional cooperation. Surprisingly, the presence of NOTCH3C455R hematopoietic cells supported the expansion of Dnmt3aR878H HSPCs in a non-cell autonomous fashion in vivo, strongly suggesting that CADASIL patients and asymptomatic carriers can be highly predisposed to DNMT3A(R882H)-driven CH. Considering that CADASIL-related NOTCH3 mutations are more frequent in the general population than anticipated (similar to 1 carrier in 400 people), the effect of these NOTCH3 mutations on CH development should be considered.

Citation

Sánchez-Lanzas, R., Barclay, J., Chardas, A., Kalampalika, F., Jiménez-Pompa, A., Gallipoli, P., & Ganuza, M. (2024). A CADASIL NOTCH3 mutation leads to clonal hematopoiesis and expansion of Dnmt3a-R878H hematopoietic clones. Leukemia, https://doi.org/10.1038/s41375-024-02464-8

• Journal Article Type: Article
• Acceptance Date: Nov 5, 2024
• Online Publication Date: Nov 13, 2024
• Publication Date: 2024
• Deposit Date: Nov 25, 2024
• Publicly Available Date: Nov 25, 2024
• Print ISSN: 0887-6924
• Electronic ISSN: 1476-5551
• Publisher: Springer Nature [academic journals on nature.com]
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1038/s41375-024-02464-8
• Keywords: STEM-CELLS; ACTIVATING MUTATIONS; LIGAND-BINDING; ATHEROSCLEROSIS; PREVALENCE; MATURATION; ENHANCER; MUSCLE; RISK