Reconstructing the lineage histories and differentiation trajectories of individual cancer cells inJAK2-mutant myeloproliferative neoplasms

Abstract

Some cancers originate from a single mutation event in a single cell. For example, blood cancers known as myeloproliferative neoplasms (MPN) are thought to originate through the acquisition of a driver mutation (most commonly JAK2-V617F) in a hematopoietic stem cell (HSC). However, when the mutation first occurs in individual patients and how it impacts the behavior of HSCs in their native context is not known. Here we quantified the impact of the JAK2-V617F mutation on the proliferation dynamics of HSCs and the differentiation trajectories of their progenies in individual MPN patients. We reconstructed the lineage history of individual HSCs obtained from MPN patients using the patterns of spontaneous somatic mutations accrued in their genomes over time. Strikingly, we found that the JAK2-V617F mutation occurred in a single HSC several decades before MPN diagnosis - at age 9±2 years in a 34-year-old patient, and at age 19±3 years in a 63-year-old patient. For each patient, we inferred the number of mutated HSCs over time and computed their fitness. The population of JAK2-mutated HSCs grew exponentially by 63±15% and 44±13% every year in the two patients, respectively. To contrast the differentiation trajectories of the JAK2-mutated HSCs with those of healthy HSCs, we simultaneously measured the full transcriptome and somatic mutations in single hematopoietic stem and progenitor cells (HSPCs). We found that the fraction of JAK2-mutant HSPCs varied significantly across different myeloid cell types within the same patient. The erythroid progenitor cells were often entirely JAK2-mutant, even when the peripheral blood JAK2-V617F allele burden was low. The novel biological insights uncovered by this work have implications for the prevention and treatment of MPN, as well as the accurate assessment of disease burden in patients. The technology platforms and computational frameworks developed here are broadly applicable to other types of hematological malignancies and cancers.

Stem cell concepts in myelodysplastic syndromes: lessons and challenges

“…Although more cases need to be assessed for the cell of origin, the multilineage (lympho-myeloid), as well as HSC clonal involvement in the cases investigated [76,77], supports that mutations in CHIP/ARCH might almost exclusively be targeted to and propagated by the multipotent HSCs compartment [6]. Importantly and similar to the studies of low-intermediate risk MDS, these studies implicate that only HSCs might possess sufficient self-renewal capacity to propagate CHIP/ARCH clones for the many years required before they have expanded sufficiently to be detected as a major clone [6,[78][79][80].…”

Immunosuppressive Cell Subsets and Factors in Myeloid Leukemias

“…Similarly to other cancers, development of leukemia is a hierarchical event [ 1 , 2 , 3 , 4 ] ( Figure 1 ). It involves a core population of tumor initiating cells (TICs)/leukemia initiating cells (LICs), as well as cancer stem cells (CSCs)/leukemia stem cells (LSCs).…”

Application of Single-Cell Approaches to Study Myeloproliferative Neoplasm Biology

“…These studies used state-of-the-art single-colony whole-genome sequencing lineage tracing approaches that rely on identification of background somatic mutations as a “molecular clock” to determine the timing of clonal expansion and disease development following acquisition of the JAK2V617F mutation. 33 , 34 With the caveat that both papers are available only as “preprints” and have not yet undergone peer review, it is striking that both studies reach a similar conclusion that the JAK2V617F mutation was reported to be acquired typically decades before disease development; remarkably, in many cases, the mutation was acquired in utero or in early childhood and yet only caused disease after many decades in adult life. In the study from the Cambridge group, 448,553 somatic mutations were identified and used to determine clonal dynamics in 843 hematopoietic colonies from 10 patients with MPN.…”

“…This study estimated the median latency between JAK2V617F acquisition and disease onset to be 31 years, with remarkable interpatient variation in fitness advantage of the MPN clone. 33 The study by Van Egeren and colleagues 34 analyzed a smaller number of colonies from 2 patients, also concluding that there was a disease latency of decades between JAK2V617F acquisition and disease onset. This long latency is particularly striking in view of the observation that many persons with normal hematopoietic parameters have evidence of a small JAK2V617F clone.…”