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Review
. 2023 Jan 26;141(4):369-379.
doi: 10.1182/blood.2021014669.

The end of the beginning: application of single-cell sequencing to chronic lymphocytic leukemia

Adi Nagler  1   2 , Catherine J Wu  1   2   3   4
Affiliations
Review

The end of the beginning: application of single-cell sequencing to chronic lymphocytic leukemia

Adi Nagler et al. Blood. .

Abstract

Single-cell analysis has emerged over the past decade as a transformative technology informative for the systematic analysis of complex cell populations such as in cancers and the tumor immune microenvironment. The methodologic and analytical advancements in this realm have evolved rapidly, scaling from but a few cells at its outset to the current capabilities of processing and analyzing hundreds of thousands of individual cells at a time. The types of profiling attainable at individual cell resolution now range from genetic and transcriptomic characterization and extend to epigenomic and spatial analysis. Additionally, the increasing ability to achieve multiomic integration of these data layers now yields ever richer insights into diverse molecular disease subtypes and the patterns of cellular circuitry on a per-cancer basis. Over the years, chronic lymphocytic leukemia (CLL) consistently has been at the forefront of genomic investigation, given the ready accessibility of pure leukemia cells and immune cells from circulating blood of patients with this disease. Herein, we review the recent forays into the application of single-cell analysis to CLL, which are already revealing a new understanding of the natural progression of CLL, the impact of novel therapies, and the interactions with coevolving nonmalignant immune cell populations. As we emerge from the end of the beginning of this technologic revolution, CLL stands poised to reap the benefits of single-cell analysis from the standpoints of uncovering fresh fundamental biological knowledge and of providing a path to devising regimens of personalized diagnosis, treatment, and monitoring.

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Conflict of interest statement

Conflict-of-interest disclosure: C.J.W. is an equity holder of BioNtech, Inc., and receives research funding from Pharmacyclics. A.N. declares no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Timeline of single-cell sequencing technology development and its applications to CLL research. (top) Major discoveries in CLL through single-cell sequencing. (bottom) Milestones in single-cell sequencing and as applied to cancer biology and tumor immunology. TIL, tumor-infiltrating lymphocytes.
Figure 2.
Figure 2.
Insights into CLL afforded by single-cell analysis. (A) Schematic of a typical CLL disease course and conceptualization of the coevolution with host immunity. Thus far, single-cell analysis has been applied to evaluate the molecular features intrinsic to CLL cells at baseline (B) as well as after therapy (C). Likewise, single-cell analysis has been applied to evaluate the native state of the CLL immune microenvironment (D) as well as the dynamic changes in immune cell populations after immune therapies (E). WBC, white blood cell.
Figure 3.
Figure 3.
Future directions for single-cell technology in CLL. Sampling from various compartments such as the blood, lymph nodes, and bone marrow (A) and sampling from early stages of the CLL disease (B) can increase our understanding of CLL development and may aid with earlier diagnosis and treatment optimization. Additionally, using a variety of high-throughput methods such as multiome profiling (C) and spatial analysis (D) can provide an in-depth understanding of CLL and immune cell regulation and function. (E) In the future, single-cell analysis potentially could inform clinical diagnostics for early disease detection, early detection of relapse, and evaluation of the functional state and potential therapeutic vulnerabilities of the relapsed cells. HSC, hematopoietic stem cell.
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