Therapy-selected clonal hematopoiesis and its role in myeloid neoplasms

Abstract

Therapy-related myeloid neoplasms (t-MN) account for approximately 10-15% of all myeloid neoplasms and are associated with poor prognosis. Genomic characterization of t-MN to date has been limited in comparison to the considerable sequencing efforts performed for de novo myeloid neoplasms. Until recently, targeted deep sequencing (TDS) or whole exome sequencing (WES) have been the primary technologies utilized and thus limited the ability to explore the landscape of structural variants and mutational signatures. In the past decade, population-level studies have identified clonal hematopoiesis as a risk factor for the development of myeloid neoplasms. However, emerging research on clonal hematopoiesis as a risk factor for developing t-MN is evolving, and much is unknown about the progression of CH to t-MN. In this work, we will review the current knowledge of the genomic landscape of t-MN, discuss background knowledge of clonal hematopoiesis gained from studies of de novo myeloid neoplasms, and examine the recent literature studying the role of therapeutic selection of CH and its evolution under the effects of antineoplastic therapy. Finally, we will discuss the potential implications on current clinical practice and the areas of focus needed for future research into therapy-selected clonal hematopoiesis in myeloid neoplasms.

Keywords: Acute myeloid leukemia; Clonal hematopoiesis; Myelodysplastic syndromes; Myeloid neoplasm; Therapy selected; Therapy-related.

Figure 1.. Timeline of investigations into the development of the SBS-MM1, a predominant signature associated with t-MN development: 2014-present.

A temporal depiction of the timeline from the first description of APOBEC and aging signature identified in 2014 through the first new unknown signature, later termed SBS-MM1, observed in 2016 and the explosion of literature in recent years demonstrating the correlation between SBS-MM1 and melphalan exposure. Abbreviations: APOBEC = apolipoprotein B editing enzyme, catalytic polypeptide; SBS = single base substitutions. [37, 82-94]

Figure 2.. Trajectories for Expansion and Transformation of Clonal Hematopoiesis Following High-Dose Melphalan and Autologous Stem Cell Transplantation.

CH may escape exposure to melphalan via leukapheresis and be autologously reinfused into an immunosuppressed recipient. The resultant t-MN bears a genomic profile similar to de novo AML and t-MN exposed to less/non-mutagenic therapies. Alternatively, fit CH clones (i.e., TP53-mutated) may survive exposure and accrue complex genomic drivers. Inset left: Single nucleotide variants will be accrued in a specific and predictable context (i.e., the mutational signature SBS-MM1). Inset center: example of a complex t-MN genome with multiple aneuploidies across each chromosome separated by vertical hatched lines. The horizontal solid black line represents the total copy number, and the horizontal hatched line represents copy number. Inset right: Example of a chromothripsis event on chromosome 5 in t-MN. The vertical lines represent structural variants breakpoints: blue = inversion, green = tandem duplication; red = deletion; black = translocation.