Clonal hematopoiesis

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.

Prevalent premalignancy

“…5 Because of its important role at different maturation stages, it is not surprising that BACH2 is deregulated in neoplastic conditions. The BACH2 gene locus is recurrently deleted in B-cell tumors, 4 and, similarly to what is reported now in MCL, patients with low BACH2 expression in tumor cells have often been found to have a worse outcome than the remaining patients with higher expression. 4,5 The activity BACH2 in normal cells is tightly regulated at different levels in a very dynamic way (see figure).…”

“…The BACH2 gene locus is recurrently deleted in B-cell tumors, 4 and, similarly to what is reported now in MCL, patients with low BACH2 expression in tumor cells have often been found to have a worse outcome than the remaining patients with higher expression. 4,5 The activity BACH2 in normal cells is tightly regulated at different levels in a very dynamic way (see figure). 5 3 Heme regulates BACH2 at the protein level, both reducing its stability and decreasing its binding to DNA.…”

“…CDKN2A, causing the negative selection of pre-B cells not bearing functional VDJ rearrangements. 4 At later maturation stages, BACH2 cooperates with BCL6, blocking the differentiation to plasma cells, suppressing BLIMP1 expression, and allowing the somatic hypermutation and class switch recombination to take place. 5 Because of its important role at different maturation stages, it is not surprising that BACH2 is deregulated in neoplastic conditions.…”

“…2,3 T he presence of clonal hematopoiesis was first inferred from the finding that X-chromosome inactivation, predicted to be a purely stochastic event, is often skewed in the blood of otherwise healthy women, a subset of whom were later shown to harbor mutations in the TET2 gene. 4 In addition, hematopoietic stem cells (HSCs) carrying preleukemic mutations can be detected in both leukemia and remission samples obtained from patients. 4 More recently, the presence of somatic variants in the blood of healthy individuals has been used to identify and characterize clonal hematopoiesis.…”

“…4 In addition, hematopoietic stem cells (HSCs) carrying preleukemic mutations can be detected in both leukemia and remission samples obtained from patients. 4 More recently, the presence of somatic variants in the blood of healthy individuals has been used to identify and characterize clonal hematopoiesis. Analysis of exome sequencing data from .30 000 people identified recurrent somatic hematologic malignancy-associated mutations in up to 10% of patients over the age of 65.…”