Elsevier

Seminars in Hematology

Volume 54, Issue 1, January 2017, Pages 43-50
Seminars in Hematology

Clonal hematopoiesis

https://doi.org/10.1053/j.seminhematol.2016.10.002Get rights and content

Abstract

Cancer results from multistep pathogenesis, yet the pre-malignant states that precede the development of many hematologic malignancies have been difficult to identify. Recent genomic studies of blood DNA from tens of thousands of people have revealed the presence of remarkably common, age-associated somatic mutations in genes associated with hematologic malignancies. These somatic mutations drive the expansion from a single founding cell to a detectable hematopoietic clone. Owing to the admixed nature of blood that provides a sampling of blood cell production throughout the body, clonal hematopoiesis is a rare view into the biology of pre-malignancy and the direct effects of pre-cancerous lesions on organ dysfunction. Indeed, clonal hematopoiesis is associated not only with increased risk of hematologic malignancy, but also with cardiovascular disease and overall mortality. Here we review rapid advances in the genetic understanding of clonal hematopoiesis and nascent evidence implicating clonal hematopoiesis in malignant and non-malignant age-related disease.

Introduction

The identification of pre-malignant states, such as cervical dysplasia and colonic tubular adenomas, and early interventions to prevent malignancy are major achievements in public health and cancer biology. However, pre-cancerous states for some hematologic malignancies, especially those of myeloid lineages, have proved elusive. In the 1990s, experimental evidence for blood clonality among healthy women raised the possibility that clonal hematopoiesis is an early step in the multistep pathogenesis of hematologic malignancy [1]. More recently, large-scale studies enumerating the common mutations in hematologic malignancies have enabled the targeted search for the cellular and molecular basis of pre-cancerous lesions in hematopoiesis. Finally, over the past few years, a number of researchers using a diversity of genomic technologies have converged on the finding that clonal hematopoiesis is indeed common, age-related, and pre-malignant.

Adult stem cells are an important but imperfect defense against the accumulation of oncogenic mutations. Most mutations, even bona fide oncogenic drivers, either occur in post-mitotic cells, or are acquired and lost harmlessly through cellular differentiation and turnover [2], [3]. Somatic genetic lesions in adult stem cells, by contrast, can accumulate and persist throughout life [4]. In aged people, the genetic diversity within the hematopoietic stem cell (HSC) compartment is significant: the human body harbors approximately 10,000–20,000 HSCs [5], and each HSC may acquire on the order of one exonic somatic mutation per decade [6]. Given a large enough population, every base pair in the genome will be mutated within at least one HSC. These mutations provide the substrate for clonal selection—the majority will have no effect on fitness, or will be deleterious and lead to clonal extinction. Rarely, mutations arise that drastically spur the expansion of the progeny of a single stem cell, leading to the state of clonal hematopoiesis.

Rapid advances in the biologic and clinical understanding of clonal hematopoiesis may reveal numerous opportunities to benefit patient care. For all that we currently know about the genetics of cancer, we may look back on the 2010s and find that we understood relatively little about the profound effects of somatic mutations and pre-malignant lesions on diverse disease states throughout the body. Here we review our current genetic understanding of clonal hematopoiesis and associations with malignant and non-malignant age-related disease.

Section snippets

Biological, clinical, and technologic convergence on clonal hematopoiesis

Studies in healthy women provided the first evidence that hematopoiesis can become oligoclonal with increasing age. Clonal skewing, inferred from non-random X-allele inactivation, was observed in peripheral leukocytes in 20%–25% of healthy women over 60 years of age [7], [8], but much less frequently in younger women. X-inactivation–based assays were also used to demonstrate that hematologic malignancies are clonal diseases, even in the absence of a clone-defining cytogenetic abnormality [9],

Clonal hematopoiesis harbors hematologic malignancy-associated mutations

Supported by these studies, several recent studies have queried genomic datasets for evidence of somatic mutations in blood DNA from tens of thousands of people, which have profoundly expanded our knowledge of the genetics and epidemiology of clonal hematopoiesis [20], [21], [22], [23], [24].

Single-nucleotide polymorphism (SNP) microarray data from blood DNA have been mined to identify acquired copy number alterations (CNAs) and uniparental disomy (aUPD) [25]. Two analyses of more than 50,000

Clonal hematopoiesis is a pre-malignant state

The somatic mutations in clonal hematopoiesis persist for years and do not appear to resolve spontaneously, unlike previous studies that found that certain translocations can be transiently present in the blood of healthy individuals [29]. Follow-up analysis of 13 patients after 4–8 years demonstrated the persistence of all somatic mutations [22]. Analyses of a small number of people directly evaluated the evolution from clonal hematopoiesis to hematologic malignancy. In two cases of

Somatic mutations and clonal expansion

The classical view of cancer genetics proposed two broad categories of genes involved in tumorigenesis: oncogenes and tumor suppressors. Landmark studies from tumor-causing viruses and human translocations led to the discovery of oncogenes which typically resulted in either abnormal signaling cascades in the mutated cells [35], [36] or else aberrantly prevented apoptosis [37]. Tumor suppressors, which acted opposite to oncogenes, were first proposed to explain the action of inherited cancer

Selection of clones following marrow injury

Clonal hematopoiesis has been identified in specific clinical contexts wherein a subset of CHIP mutations appears to undergo positive selection. Aplastic anemia is an immune-mediated bone marrow failure disorder wherein autoreactive T cells suppress hematopoietic stem and/or progenitor cells. Clonal hematopoiesis has long been recognized as a common but surprising finding in aplastic anemia [67] and people with aplastic anemia are at markedly elevated risk for paroxysmal nocturnal

Clonal hematopoiesis of indeterminate potential, a provisional diagnosis

In order to define the pre-malignant state of clonal hematopoiesis in clinical practice, and to distinguish it from MDS, we have proposed a working definition for CHIP [91] (Table 1). Individuals with CHIP have a detectable clonal mutation or copy number alteration associated with hematologic neoplasia in the blood or bone marrow, and lack a known hematologic malignancy or defined clonal entity such as PNH, MBL, or MGUS. The lower limit for allele fraction is provisionally set at 2%, a cutoff

CHIP and age-associated inflammatory disease: Correlation or causation?

Pre-malignant states are generally assumed to have no impact on health in the absence of progression to frank cancer. Several reasons suggest that clonal mutations in HSCs might lead to organ dysfunction in the absence of malignancy. First, clonal selection and function are uncoupled: HSC with clonal advantage are not promoted based on the quality of their differentiated effector progeny, but instead at the level of stem cell self-renewal and survival [96]. Second, unlike solid tissues,

Conclusions

Clonal mutations in genes that are recurrently mutated in hematologic malignancies are commonly detected in the blood of otherwise healthy aging people. Rapid progress in our understanding of clonal hematopoiesis raises questions spanning from stem cell biology to medicine. While model systems affirm a self-renewal advantage for HSCs with DNMT3A and TET2 mutations, the mechanisms of clonal expansion are poorly understood for these and most other CHIP mutations. It also remains to be seen how

Conflicts of interest

None.

Acknowledgments

This work was supported by grants from the NIH (R01 HL082945, R24 DK099808), the Department of Defense, the Edward P. Evans Foundation, and the Leukemia and Lymphoma Society. SJ is supported by the Training Program in Molecular Hematology T32 training grant (Brigham and Women’s Hospital) and the Burroughs Wellcome Fund Career Award for Medical Scientists.

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