Clonal Evolution of High-Risk Chronic Lymphocytic Leukemia: A Contemporary Perspective

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.

Simulating Interclonal Interactions in Diffuse Large B-Cell Lymphoma

“…A logistic function was chosen to describe the general behavior of DLBCL cells, as it can be relevant when considering a spatially extended system in which proliferation is constrained by available space [36]. Moreover, logistic growth has been observed in clonal equilibrium associated with chronic lymphocytic leukemia, another hematological malignancy [37]. For initial computational simulations, it was assumed that the resistant cells would have a smaller rate constant than the sensitive variant.…”

Therapeutic Applications of the CRISPR-Cas System

“…The development of the CRISPR-Cas9 system suggested that researchers might be given a new method for cancer treatment [ 42 ]. Given that cancer is a genetic abnormality caused by a series of genetic alterations, it is reasonable to believe that repairing oncogenic genome/epigenome aberrations using CRISPR-Cas9 could be a promising cancer treatment modality [ 43 ]. Furthermore, by using the CRISPR system, existing anticancer therapies can be improved in terms of high precision and safety, and broad applications including anticancer drug development research are possible [ 44 ].…”

Cellular Therapy in High-Risk Relapsed/Refractory Chronic Lymphocytic Leukemia and Richter Syndrome

“…The wide range in incidence may be explained by the heterogeneous mutational status of CLL patients from different studies. In fact, specific biomarkers (e.g., NOTCH1, TP53 abnormalities, and trisomy 21) coupled with definite microenvironmental interactions associate to a higher risk of RS transformation ( 5 , 6 ). Disease progression and high-grade transformation are a frequent cause of targeted therapy discontinuation in trial ( 3 , 7 ) and non-trial ( 8 – 11 ) populations.…”