Clonal hematopoiesis is clonally unrelated to multiple myeloma and is associated with specific microenvironmental changes
Multiple myeloma (MM) initiation is dictated by genomic events. However, its progression from asymptomatic stages to an aggressive disease that ultimately fails to respond to treatments is also dependent on changes of the tumor microenvironment (TME). Clonal hematopoiesis of indeterminate potential (CHIP) is a prevalent clonal condition of the hematopoietic stem cell whose presence is causally linked to a more inflamed microenvironment. Here, we demonstrate in 106 patients with MM that CHIP is frequently coexisting with MM at diagnosis, associates with a more advanced Revised International Staging System stage and higher age, and has a nonsignificant trend toward lower median hemoglobin. In our cohort, the 2 conditions do not share a clonal origin. Single-cell RNA sequencing in 16 patients with MM highlights significant TME changes when CHIP is present: decreased naive T cells, a proinflammatory TME, decreased antigen-presenting function by dendritic cells, and expression of exhaustion markers in CD8 cells. Inferred interactions between cell types in CHIP-positive TME suggested that especially monocytes, T cells, and clonal plasma cells may have a prominent role in mediating inflammation, immune evasion, and pro-survival signals in favor of MM cells. Altogether, our data reveal that, in the presence of CHIP, the TME of MM at diagnosis is significantly disrupted in line with what is usually found in more advanced disease, with potential translational implications. Our data highlight the relevance of this association and prompt for further studies on the modifier role of CHIP in the MM TME.
Authors
- Francesca Lazzaroni (ORCID: https://orcid.org/0000-0001-5767-7846)
- Alessio Marella (ORCID: https://orcid.org/0000-0002-2897-4523)
- Francesco Passamonti (ORCID: https://orcid.org/0000-0001-8068-5289)
- Giancarlo Castellano (ORCID: https://orcid.org/0000-0002-5715-7733)
- Marzia Barbieri (ORCID: https://orcid.org/0000-0002-9027-1888)
- Antonio Matera (ORCID: https://orcid.org/0000-0002-9348-1792)
- Silvia Lonati (ORCID: https://orcid.org/0009-0001-3034-9874)
- Claudio De Magistris
- Domenica Ronchetti (ORCID: https://orcid.org/0000-0002-4824-3445)
- Ilaria Silvestris
- Antonino Neri (ORCID: https://orcid.org/0000-0001-9047-5912)
- Niccolò Bolli (ORCID: https://orcid.org/0000-0002-1018-5139)
- Loredana Pettine (ORCID: https://orcid.org/0000-0001-9553-2082)
- Marta Lionetti (ORCID: https://orcid.org/0000-0002-3342-9095)
- Valentina Traini (ORCID: https://orcid.org/0009-0008-5875-2623)
- Stefania Pioggia
- Sonia Fabris (ORCID: https://orcid.org/0000-0003-1341-0503)
- Elisa Taìana (ORCID: https://orcid.org/0000-0003-4940-1318)
- Akihiro Maeda (ORCID: https://orcid.org/0000-0003-4797-0314)
- G. Fabbiano (ORCID: https://orcid.org/0000-0002-3554-3318)
- Matteo Da Vià (ORCID: https://orcid.org/0000-0002-5396-6584)
- Alfredo Marchetti
- Alessandra Cattaneo (ORCID: https://orcid.org/0000-0002-4500-6540)
- Marta Tornese
- Margherita Scopetti
- Claudia Leoni (ORCID: https://orcid.org/0009-0004-8346-0826)
Institutions
- University of Milan (IT)
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
- Ospedale Maggiore (IT)
- Azienda Sanitaria Unità Locale di Reggio Emilia (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- European Institute of Oncology (IT)
Publication Details
- Journal
- Blood
- Published
- 2025-03-20
- DOI
- https://doi.org/10.1182/blood.2024026236
- Citations
- 5
- Primary Topic
- Multiple Myeloma Research and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 8.85