Impact of Clonal Hematopoiesis on the Carcinogenic Process of Multiple Myeloma

Author:

Koh Youngil1ORCID,Park Changhee1ORCID,Cho Gayeon2,Ryu Gangpyo3,Park Jeongmin3,Yoon Hyundong3,Oh Yu Mi4,Lee Chansub5,An Hongyul6,Sun Choong-Hyun7,Jung Sung-Hoon8,Lee Je-Jung9ORCID,Kim Bum Suk10,Byun Ja Min1ORCID,Shin Dong-Yeop1ORCID,Hong Junshik1,Kim Inho1,Yoon Sung-Soo5ORCID,Nachun Daniel11ORCID,Maurer Taylor11ORCID,Choi Su-Yeon12,Kim Seok Jin13ORCID,Kim Chan-Hyuk14,Kim Kihyun13,Cho Sung-Yup3,Jaiswal Siddhartha11ORCID,Kim Jong2ORCID

Affiliation:

1. Seoul National University Hospital

2. Pohang University of Science and Technology (POSTECH)

3. Seoul National University

4. Seoul National University College of Medicine

5. Department of Internal Medicine, Seoul National University Hospital

6. Genome Opinion Incorporation

7. Nobo Medicine Inc.

8. Chonnam National University

9. Chonnam National University Hwasun Hospital

10. MOGAM Institute for Biomedical Research

11. Stanford University

12. Seoul National University Healthcare System Gangnam Center

13. Samsung Medical Center

14. Korea Advanced Institute of Science and Technology (KAIST)

Abstract

Abstract

Clonal hematopoiesis (CH), a phenomenon linked to aging, correlates with inflammation and myeloid malignancies. Here, we explore the interaction of CH, with terminally differentiated lymphoid malignancy, and multiple myeloma (MM). Analysis of CH in clinical cohorts revealed a higher prevalence among MM patients and a lower deep response to proteasome inhibitors. By utilizing the bone marrow samples from MM patients with CH, single-cell transcriptome analyses indicated frequent interaction between CH and MM cells, mediated by CCR10-CCL2, resulting in the upregulation of the MAPK pathway and angiogenesis, findings corroborated by exosome RNA analysis. Conditioned media from TET2 knockdown macrophages significantly enhanced MM cell proliferation compared to that from wild-type cells, an effect reversible by a CCR10 inhibitor. Our results underscore the pivotal role of TET2 CH in driving CCR10-high myeloma progression through paracrine oncogenic effects via exosomal interactions on CCR10, suggesting its potential as a therapeutic target.

Publisher

Springer Science and Business Media LLC

Reference62 articles.

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