Abstract
Clonal evolution represents the natural process through which cancer cells continuously search for phenotypic advantages that enable them to develop and expand within microenvironmental constraints. In chronic lymphocytic leukemia (CLL), clonal evolution underpins leukemic progression and therapeutic resistance, with differences in clonal evolutionary dynamics accounting for its characteristically diverse clinical course. The past few years have witnessed profound changes in our understanding of CLL clonal evolution, facilitated by a maturing definition of high-risk CLL and an increasing sophistication of next-generation sequencing technology. In this review, we offer a modern perspective on clonal evolution of high-risk CLL, highlighting recent discoveries, paradigm shifts and unresolved questions. We appraise recent advances in our understanding of the molecular basis of CLL clonal evolution, focusing on the genetic and non-genetic sources of intratumoral heterogeneity, as well as tumor-immune dynamics. We review the technological innovations, particularly in single-cell technology, which have fostered these advances and represent essential tools for future discoveries. In addition, we discuss clonal evolution within several contexts of particular relevance to contemporary clinical practice, including the settings of therapeutic resistance to CLL targeted therapy and immunotherapy, as well as Richter transformation of CLL to high-grade lymphoma.
Highlights
Clonal heterogeneity and evolution are among the most fundamental properties of cancer
We provided a contemporaneous account of clonal evolution as it relates to high-risk chronic lymphocytic leukemia (CLL), highlighting recent discoveries that have offered novel insight
We have come to appreciate that with each therapeutic innovation comes the inevitable problem of therapeutic resistance, which can only be tackled through an exhaustive understanding of clonal evolution
Summary
Clonal heterogeneity and evolution are among the most fundamental properties of cancer. CLL is characterized by clinical heterogeneity that encompasses a range of disease trajectories including rapid progression, treatment refractoriness and high-grade transformation at one end of the spectrum [4, 5], to a highly stable clinical course or even spontaneous disease regression at the opposite end [6, 7] This allows tumor evolution to be studied across a range of differing clinical contexts. Advances in bulk sequencing and more recently integrative single-cell sequencing technology have facilitated the longitudinal study of CLL clonal evolution in this patient group These studies have illuminated our understanding of CLL clonal architecture and the complex clonal evolutionary dynamics that give rise to CLL progression, resistance to different CLL treatments and high-grade transformation, revealing diverse biological processes and novel mechanisms.
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