Reconstructing the Lineage Histories and Differentiation Trajectories of Individual Cancer Cells in Myeloproliferative Neoplasms

Abstract

Summary Some cancers originate from a single mutation event in a single cell. Blood cancers known as myeloproliferative neoplasms (MPNs) are thought to originate when a driver mutation is acquired by a hematopoietic stem cell (HSC). However, when the mutation first occurs in individuals and how it affects the behavior of HSCs in their native context is not known. Here we quantified the effect of the JAK2 -V617F mutation on the self-renewal and differentiation dynamics of HSCs in treatment-naive individuals with MPNs and reconstructed lineage histories of individual HSCs using somatic mutation patterns. We found that JAK2- V617F mutations occurred in a single HSC several decades before MPN diagnosis—at age 9 ± 2 years in a 34-year-old individual and at age 19 ± 3 years in a 63-year-old individual—and found that mutant HSCs have a selective advantage in both individuals. These results highlight the potential of harnessing somatic mutations to reconstruct cancer lineages.

Germline risk of clonal haematopoiesis

“… 104 ). Of note, these studies each identified sets of MZ twins that shared identical CH mutations ( KDM6A p.Q692X and DNMT3A p.R598X in the UK cohort 103 and SRSF2 p.P95H and c.912_916delCTGGT in DNMT3A in the Denmark cohort 104 ), suggesting these mutations occurred in utero 103 ; several subsequent studies of patients with MPNs have identified JAK2 V617F and DNMT3A mutations that similarly arose during embryogenesis or childhood 105 , 106 . Taken together, these twin studies provide no evidence for common, strong germline effects on the development of CHIP in the populations studied.…”

Adolescent animal product intake in relation to later prostate cancer risk and mortality in the NIH-AARP Diet and Health Study

“…PCa because the prostate may be more susceptible to deleterious exposures while it is growing and developing rapidly [16]. This hypothesis is supported by several observations, including the finding of stronger associations for early-life than for adult exposures (e.g., hig-fat diet) with prostate lesion development in animal studies [17,18]; the mathematical estimation of PCa initiation (i.e., first genomic alteration) as early as puberty in some men [19], similar to estimated for a growing number of other cancers [20,21]; the observation of PCa precursor lesions and small PCa foci in men as young as their twenties and thirties in human histologic studies [22][23][24][25][26][27]. Additional supportive observations include the divergence in prostate lesion prevalence [28], as well as in PCa incidence and mortality [29], by race in men in their thirties and forties, and the observation of positive associations for characteristics influenced by early-life diet and other early-life exposures (e.g., height and timing of puberty [30,31]) with PCa incidence and mortality [32][33][34][35][36].…”

Inflammatory Pathophysiology as a Contributor to Myeloproliferative Neoplasms

“…A notable feature of MPNs is their diversity of disease phenotypes. MPNs may present as ET, PV, or PMF, often following years to decades of asymptomatic clonal hematopoiesis ( 13 , 14 , 16 , 17 ). The malignant clones in the vast majority of MPN patients harbor mutations in JAK2 , calreticulin ( CALR ), or MPL ( 18 ).…”

“…Inflammation is considered a factor that may promote MPN disease development, progression and/or lead to poorer prognosis overall. The recent findings that clonal hematopoiesis is frequent among adult humans, that JAK2 V617F is among the most common mutations found in asymptomatic clonal hematopoiesis, and that, impressively, clonal JAK2 V617F is most frequently acquired in childhood or even in utero, suggest that some biological selective process is necessary to transform asymptomatic JAK2 V617F mutant clones into overt MPNs (13)(14)(15)(16)(17). Chronic inflammation in the bone marrow or in the systemic circulation could contribute to the slow selection for eventually pathogenic mutant clones.…”