Biology subjects

Kapadia, C. D.

Publications and source records attributed to Kapadia, C. D..

3 recordsLinked to original sources

bioRxiv2025

JAK2 signalling to HNRNPA1 represses retrotransposon activity in haematopoietic stem cells

Retrotransposon expression must be tightly controlled, particularly in long-lived multipotent stem cells, to prevent deleterious consequences including insertional mutations. Several mechanisms are known to repress retrotransposon transcription during development which are generally thought to persist thereafter. However, integration of retrotransposable elements into host genomes has also provided a major source of genetic variation across evolution. This has generated many sequences that have acquired advantageous host functions, but little is known about retrotransposon expression and mobility in adult stem cells or about how these processes might be dynamically regulated. Here we describe the landscape of somatic retrotransposition in haematopoietic stem cells and identify a previously unrecognised pathway which links cytokine signalling, RNA-modulating HNRNP complexes and repression of retrotransposon activity. Activation of JAK2, by thrombopoietin or gain-of-function JAK2 mutations, triggers tyrosine phosphorylation of HNRNPA1 that represses expression of ERVs, LINEs and SINEs and reduces insertional mutagenesis. This pathway coordinates retrotransposon activity with cellular context and state and provides a mechanism for protecting the haematopoietic stem cell genome.

cell biology↗

bioRxiv2024

Clonal dynamics and somatic evolution of haematopoiesis in mouse

Haematopoietic stem cells maintain blood production throughout life. While extensively characterised using the laboratory mouse, little is known about how the population is sustained and evolves with age. We isolated stem cells and progenitors from young and old mice, identifying 221,890 somatic mutations genome-wide in 1845 single cell-derived colonies, and used phylogenetic analysis to infer the ontogeny and population dynamics of the stem cell pool. Mouse stem cells and progenitors accrue [~]45 somatic mutations per year, a rate only about 2-fold greater than human progenitors despite the vastly different organismal sizes and lifespans. Phylogenetic patterns reveal that stem and multipotent progenitor cell pools are both established during embryogenesis, after which they independently self-renew in parallel over life. The stem cell pool grows steadily over the mouse lifespan to approximately 70,000 cells, self-renewing about every six weeks. Aged mice did not display the profound loss of stem cell clonal diversity characteristic of human haematopoietic ageing. However, targeted sequencing revealed small, expanded clones in the context of murine ageing, which were larger and more numerous following haematological perturbations and exhibited a selection landscape similar to humans. Our data illustrate both conserved features of population dynamics of blood and distinct patterns of age-associated somatic evolution in the short-lived mouse.

genomics↗

bioRxiv2024

Clonal evolution of hematopoietic stem cells after cancer chemotherapy

Normal hematopoietic stem and progenitor cells (HSPCs) inherently accumulate somatic mutations and lose clonal diversity with age, processes implicated in the development of myeloid malignancies1. The impact of exogenous stressors, such as cancer chemotherapies, on the genomic integrity and clonal dynamics of normal HSPCs is not well defined. We conducted whole-genome sequencing on 1,032 single-cell-derived HSPC colonies from 10 patients with multiple myeloma (MM), who had undergone various chemotherapy regimens. Our findings reveal that melphalan treatment distinctly increases mutational burden with a unique mutation signature, whereas other MM chemotherapies do not significantly affect the normal mutation rate of HSPCs. Among these therapy-induced mutations were several oncogenic drivers such as TET2 and PPM1D. Phylogenetic analysis showed a clonal architecture in post-treatment HSPCs characterized by extensive convergent evolution of mutations in genes such as TP53 and PPM1D. Consequently, the clonal diversity and structure of post-treatment HSPCs mirror those observed in normal elderly individuals, suggesting an accelerated clonal aging due to chemotherapy. Furthermore, analysis of matched therapy-related myeloid neoplasm (t-MN) samples, which occurred 1-8 years later, enabled us to trace the clonal origin of t-MNs to a single HSPC clone among a group of clones with competing malignant potential, indicating the critical role of secondary mutations in dictating clonal dominance and malignant transformation. Our findings suggest that cancer chemotherapy promotes an oligoclonal architecture with multiple HSPC clones possessing competing leukemic potentials, setting the stage for the selective emergence of a singular clone that evolves into t-MNs after acquiring secondary mutations. These results underscore the importance of further systematic research to elucidate the long-term hematological consequences of cancer chemotherapy.

cancer biology↗