Extraction of mitochondrial DNA mutations from bulk RNA-seq data in CLL.

Assessment of deconvolution performance of synthetic chimeric cell populations in in-silico mixing experiments.

Longitudinal changes of somatic nuclear and mitochondrial DNA mutations in genetically stable CLL.

Co-evolution of somatic nuclear and mitochondrial DNA mutations in AML.

Identification of cell types and tracking of mitochondrial DNA mutations in immunosuppression tapering (IST) cohort using ASAP-seq.

Identification of high-confidence mitochondrial DNA mutations for Tapestri analysis.

Mutations targeted using single cell DNA sequencing in AML1012.

Deconvolution and identification of AML phenotypes in bone marrow using ASAP-seq.

Identification of AML subclones using mitochondrial DNA (mtDNA) mutations.

Blood and bone marrow counts of immunosuppression tapering (IST) cohort from routine clinical measurements.

Mitochondrial and somatic nuclear DNA mutations identified in CLL using single cell DNA sequencing.

Differential phenotypes of physiologic (donor-) and malignant hematopoietic (recipient-derived) cells.

Longitudinal changes of somatic nuclear and mitochondrial DNA mutations in naturally progressing CLL.

Participants of ETCTN/CTEP 10026 studied with ASAP-seq.

Supplementary Figures 1-20 and Supplementary Tables 1-10, Supplementary notes

Immunosuppression tapering cohort.

Co-segregation of mitochondrial and somatic nuclear DNA mutations in CLL.

Longitudinal changes of somatic nuclear and mitochondrial DNA mutations in evolving CLL.

Tracking co-evolution of somatic nuclear and mitochondrial DNA mutations in CLL and AML using single cell DNA and protein sequencing (Tapestri).

Ribosomal protein mutations are increasingly associated with cancer risk and thought to perturb ribosome function. At the same time, they reportedly activate p53, a critical anti-cancer barrier. To determine how these mutations overcome this protective block to enable tumorigenesis, we generate an in vivo model of the hotspot ribosomal protein RPS15-S138F mutation identified as a putative driver of chronic lymphocytic leukemia. Under pre-leukemic conditions, this mutation induces ribosome biogenesis defects and altered translation resulting in oxidative stress, DNA damage and induction of a p53-dependent response that promote initial cellular hypo-proliferation. However, a subset of aged mice with mutated Rps15 eventually develop B-cell leukemia (37% penetrance), which exhibits increased Myc activity with strong pro-survival and proliferation signatures. Mutant RPS15 thus induces both hypo- and hyper-proliferative signals, initially weighted towards cell cycle arrest; and that through translational rewiring, oxidative stress, DNA damage response defects and genomic instability set the stage for the acquisition of additional driving mutations, such as TP53 deletion, that can overcome this cell cycle block to trigger tumorigenesis.