From Clonal Hematopoiesis to Therapy-Related Myeloid Neoplasms: The Silent Way of Cancer Progression

Abstract

Clonal hematopoiesis (CH) has been recognized as a predisposing factor for the development of myeloid malignancies. Its detection has been reported at different frequencies across studies, based on the type of genome scanning approach used and the population studied, but the latest insights recognize its virtual ubiquitous presence in older individuals. The discovery of CH in recent years paved the way for a shift in the paradigm of our understanding of the biology of therapy-related myeloid malignancies (t-MNs). Indeed, we moved from the concept of a treatment-induced lesion to a model where CH precedes the commencement of any cancer-related treatment in patients who subsequently develop a t-MN. Invariant patterns of genes seem to contribute to the arising of t-MN cases, with differences regarding the type of treatment received. Here, we review the principal studies concerning CH, the relationship with myeloid progression and the mechanisms of secondary t-MN development.

Hematological disorders after salvage PARPi treatment for ovarian cancer: Cytogenetic and molecular defects and clinical outcomes

“…These conditions can be divided into: (a) cytopenic states (ICUS and CCUS) or noncytopenic states (IDUS, CHIP, CCAUS) and (b) states with an unknown or negative mutation status (ICUS and IDUS) or cases with known (documented and relevant) somatic mutations/cytogenetic abnormalities (CHIP, CCUS and CCAUS). All of these conditions can persist without clinical manifestation or progression, but can develop into overt MDS 21,22 . Hematological procedures were performed according to internal institutional diagnostic and clinical guidelines.…”

“…All of these conditions can persist without clinical manifestation or progression, but can develop into overt MDS. 21 , 22 Hematological procedures were performed according to internal institutional diagnostic and clinical guidelines.…”

Clonal Hematopoiesis: Role in Hematologic Non-Hematologic

“… 96 Cytopenia is defined as a condition in which the patients must have, for at least six months, hemoglobin, platelets and neutrophil counts less than 11g/dL, 100x10 9 /L and 1.5x10 9 /L, respectively. 234 If a patient with cytopenia does not fulfil the criteria for diagnosis of myelodysplastic syndrome, it is most probably affected by the so-called idiopathic cytopenia of undetermined significance (ICUS). 235 When a subject with ICUS displays a somatic mutation in myelodysplasia-associated genes, in the absence of diagnostic criteria for MDS, the condition is considered a clonal cytopenia of undetermined significance (CCUS).…”

The Interactome between Metabolism and Gene Mutations in Myeloid Malignancies

“…The prognostic role of TET2 lesions has been controversial because of their high frequency, their heterogeneity, and the variability of the concurrent genetic lesions, all characteristics contributing to shaping the fate of individual patients and ultimately precluding a clear genotype/phenotype association [30]. Moreover, the discovery of mutations in myeloid genes in normal individual (referred to as CHIP, clonal hematopoiesis of indeterminate potential) at frequencies linearly correlated with age (age-related clonal hematopoiesis, ARCH) shed light on the process of myeloid evolution and provided clues on clonality and subclonal hierarchies in myeloid malignancies [31]. The occurrence of TET2 mutations in CHIP/ARCH is another confirmation of the importance of this gene in cell development.…”

“…The occurrence of TET2 mutations in CHIP/ARCH is another confirmation of the importance of this gene in cell development. Together with additional sex combs-like 1 (ASXL1) and DNA methyltransferase 3 alpha (DNMT3A) genes, TET2 represents one of the most frequently mutated genes in CHIP/ARCH so that the three genes are referred to with the acronym DAT (DNMT3A/ASXL1/TET2) [31]. This finding, as well as the ubiquitous presence of TET2 mutations in hematological malignancies, indicate that TET2 lesions are mainly ancestral events occurring early in the course of the disease and contribute to the creation of a so-called "mutator phenotype", by giving to the clone a proclivity for the acquisition of additional molecular lesions [32].…”