Clonal hematopoiesis is clonally unrelated to multiple myeloma and is associated with specific microenvironmental changes
Abstract
Abstract 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.
Article Details
Authors (26)
Marta Lionetti
7University of Milan, Milano, Italy
Margherita Scopetti
1Department of Oncology and Hematology-Oncology, University of Milan, Milan, Italy
Antonio Matera
7University of Milan, Milano, Italy
Akihiro Maeda
6Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy
Alessio Marella
7University of Milan, Milano, Italy
Francesca Lazzaroni
2Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
Giancarlo Castellano
5Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Sonia Fabris
2Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
Stefania Pioggia
6Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy
Silvia Lonati
1Department of Oncology and Hematology-Oncology, University of Milan, Milan, Italy
Alfredo Marchetti
1Department of Oncology and Hematology-Oncology, University of Milan, Milan, Italy
Alessandra Cattaneo
3Flow Cytometry Laboratory, Clinical Pathology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
Marta Tornese
3Flow Cytometry Laboratory, Clinical Pathology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
Antonino Neri
Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
Claudia Leoni
Loredana Pettine
16Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
Valentina Traini
1Department of Oncology and Hematology-Oncology, University of Milan, Milan, Italy
Ilaria Silvestris
1Department of Oncology and Hematology-Oncology, University of Milan, Milan, Italy
Marzia Barbieri
2Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
Giuseppina Fabbiano
2Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
Domenica Ronchetti
4University of Milan, Department of Oncology and Hemato-oncology, Milan, Italy
Elisa Taiana
1Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico
Claudio de Magistris
6Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy
Matteo C. Da Vià
3Hematology Section, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
Francesco Passamonti
University of Milan, Milan
Niccolò Bolli
1Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico