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Longitudinal single-cell dynamics of mitochondrial mutations in chronic lymphocytic leukemia mirror disease history

ABSTRACT: Mitochondrial mutations have the potential to act as natural barcodes that allow the tracking of heterogenous cell populations at the single cell level, but thus far, the dynamics of mitochondrial mutations across time and tissue compartments have not been extensively studied. This dataset was generated using mtscATAC-seq to track mitochondrial mutations in peripheral blood, bone marrow and lymph node from 9 patients with chronic lymphocytic leukemia (CLL) across different clinical scenarios. Our in-depth analysis reveals different patterns of dynamisms in mitochondrial mutations in patients undergoing watchful waiting, chemotherapy with fludarabine, cyclophosphamide and rituximab (FCR), allogeneic stem cell transplantation, ibrutinib treatment or transformation to Richter’s syndrome. We provide evidence that mitochondrial mutations can link CLL subclones with distinct chromatin cell states. Mitochondrial mutations appear to recapitulate disease history in CLL, providing patient-level support of the concept of in vivo natural barcodes as a means for understanding clonal dynamics in cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE163579 | GEO | 2021/06/09

REPOSITORIES: GEO

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Project description:During many years, chemo-immunotherapy fludarabine-cyclophosphamide-rituximab (FCR) was considered as the gold standard for the first line treatment of medically fit patients with symptomatic B-chronic lymphocytic leukemia (CLL). Over the last decade, targeted biotherapies have revolutionized the management of B-CLL patients' treatment and almost entirely supplanted FCR. However, no biomarker still exists to predict the complete remission (CR) with undetectable minimal residual disease (uMRD), which remains so far the best predictive factor for survival. Circulating miRNAs represent a class of molecular biomarkers which expression is altered in hematological disorders including B-CLL. Our present study aimed at identifying before treatment circulating miRNAs that predict the treatment outcome in previously untreated B-CLL patients (NCT 01370772, https://clinicaltrials.gov/ct2/show/NCT01370772). Using hierarchical clustering of miRNA expression profiles discriminating 8 patients who achieved CR with bone marrow (BM) uMRD, from 8 patients who do not achieved CR and displayed detectable BM MRD, we identified 25 miRNAs differentially expressed before treatment. The expression of 11 representative miRNAs was further validated on a larger cohort (n=123). Based on the dosage of 5 miRNAs at diagnosis, a decision tree was constructed to predict treatment outcome. Our results identified 6 groups of patients with a distinct probability of being CR with BM uMRD to FCR treatment, ranging from 72% (miR-125b, miR-15b and miR-181c high) to 4% (miR-125b and miR-193b low). Progression-free survival (PFS) was significantly different between the established groups (p=0.019). None of the patients displaying high expression levels of miR-125b, miR-15b and miR-181c (HHH group) relapsed during the follow-up of the study. In contrast, patients with miR-15b low and miR-412 high (HLH group), and patients with low expression levels of miR-125b and miR-193b (LL group) demonstrated a significant low PFS. By RNA sequencing blood at diagnosis, we compared mRNA expression profiles of these three groups, achieving or not CR with uMRD. We identified that patients relapsing after treatment are characterized by significant enrichment of gene signatures related to cell cycle, MYC target genes, metabolism and translation regulation at diagnosis. Conversely, patients achieving CR with uMRD displayed significant enrichment in genes related to communication between CLL cells and the microenvironment, immune system activation and upregulation of polycomb PRC2 complex target genes at diagnosis. Our results suggest that blood miRNAs are potent predictive biomarkers for treatment efficacy of FCR and might be implicated in the FCR efficacy in B-CLL patients. Further investigations could establish whether these miRNAs might also be used to stratify patients for new-generation treatments. Overall, our work provides insight into unmet need for the treatment of B-CLL patients and identified pathways potentially predictive of patients’ remission.

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Longitudinal single-cell dynamics of mitochondrial mutations in chronic lymphocytic leukemia mirror disease history

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