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Publications

Single-Cell DNA Sequencing Reveals an Evolutionary Pattern of CHIP in Transplant Eligible Multiple Myeloma Patients


Enrica Borsi, Ilaria Vigliotta, Andrea Poletti, Gaia Mazzocchetti, Vincenza Solli, Luca Zazzeroni, Marina Martello, Silvia Armuzzi, Barbara Taurisano, Ajsi Kanapari, Ignazia Pistis, Elena Zamagni, Lucia Pantani, Serena Rocchi, Katia Mancuso, Paola Tacchetti, Ilaria Rizzello, Simonetta Rizzi, Elisa Dan, Barbara Sinigaglia
MDPI Apr 2024
Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) refers to the phenomenon where a hematopoietic stem cell acquires fitness-increasing mutation(s), resulting in its clonal expansion. CHIP is frequently observed in multiple myeloma (MM) patients, and it is associated with a worse outcome. High-throughput amplicon-based single-cell DNA sequencing was performed on circulating CD34+ cells collected from twelve MM patients before autologous stem cell transplantation (ASCT). Moreover, in four MM patients, longitudinal samples either before or post-ASCT were collected. Single-cell sequencing and data analysis were assessed using the MissionBio Tapestri® platform, with a targeted panel of 20 leukemia-associated genes. We detected CHIP pathogenic mutations in 6/12 patients (50%) at the time of transplant. The most frequently mutated genes were TET2, EZH2, KIT, DNMT3A, and ASXL1. In two patients, we observed co-occurring mutations involving an epigenetic modifier (i.e., DNMT3A) and/or a gene involved in splicing machinery (i.e., SF3B1) and/or a tyrosine kinase receptor (i.e., KIT) in the same clone. Longitudinal analysis of paired samples revealed a positive selection of mutant high-fitness clones over time, regardless of their affinity with a major or minor sub-clone. Copy number analysis of the panel of all genes did not show any numerical alterations present in stem cell compartment. Moreover, we observed a tendency of CHIP-positive patients to achieve a suboptimal response to therapy compared to those without. A sub-clone dynamic of high-fitness mutations over time was confirmed.

VIEW

Area

Heme

Institution Type

Academia

Indication / Modality

Multiple Myeloma

Goal of Study

Clinical Profiling, CHIP

Key Genes

TET2, DNMT3A, TP53, EZH2, ASXL1, FLT3, RUNX1, KRAS, PTPN11, SRSF2, SF3B1

PAD Project

No

Analytes Assessed

SNV, InDels

Species

Human

Panel Used

Catalog AML Panel

Proof Point Demonstrated

Co-occurrence, Clonality, Phylogeny, Zygosity
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