Leukemia (2023)
Abstract
Myeloproliferative neoplasms are characterized by the acquisition at the hematopoietic stem cell level of driver mutations targeting the JAK/STAT pathway. In addition, they also often exhibit additional mutations targeting various pathways such as intracellular signalling, epigenetics, mRNA splicing or transcription. The natural history of myeloproliferative neoplasms is usually marked by a chronic phase of variable duration depending on the disease subtype, which can be followed by an accelerated phase or transformation towards more aggressive diseases such as myelofibrosis or acute leukemia. Besides, recent studies revealed important new information about the rates and mechanisms of sequential acquisition and selection of mutations in hematopoietic cells of myeloproliferative neoplasms. Better understanding of these events has been made possible in large part with the help of novel techniques that are now available to precisely decipher at the single cell level both the clonal architecture and the mutation-induced cell modifications. In this review, we will summarize the most recent knowledge about the mechanisms leading to clonal selection, how clonal architecture complexity can explain disease heterogeneity, and the impact of clonal evolution on clinical evolution.
Introduction
BCR::ABL1-negative myeloproliferative neoplasms (MPNs) include essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). In these chronic hematological malignancies, the main short-term risk is the occurrence of thrombosis but a subset of patients may also evolve into secondary myelofibrosis, myelodysplastic syndrome or acute myeloid leukemia in the long run. However, the risk of long term evolution is heterogeneous between MPN subtypes: recent retrospective studies suggest that a high proportion of PV patients (up to 75% in 13 years) may experience progression to secondary myelofibrosis or AML [1], while in ET only a minority of patients experience clonal evolution and deterioration of MPN. The clinical course of MPNs is therefore characterized by a hitherto not fully understood nor accurately predicted inter-patient heterogeneity.
In the recent years, disease heterogeneity has been mainly linked to the diversity of genetic lesions found in patients’ hematopoietic stem cells (HSC). Indeed, MPNs represent a model of sequential acquisition of genetic abnormalities over time, allowing the study of the influence of environmental and intrinsic factors on tumor shape. Numerous studies have shown that precise genetic characterization of the disease can help to evaluate its prognosis [2] as the number and type of mutations are the main criteria considered to predict the outcome of patients. Indeed, recent prognostic scoring systems include the mutational pattern [3,4,5]. Dissecting the prognostic impact of diverse molecular markers allows a better understanding of the heterogeneity of tumor cells and demonstrates its predominant role in MPN evolution. Furthermore, implementation of new sequencing techniques at the single-cell level allows more precise characterization of complex molecular patterns associated with disease heterogeneity. Despite an improved understanding of the clonal architecture of MPNs over the past years, the mechanisms leading to clonal selection once the mutations are acquired remain poorly understood. In several types of cancers, a clear role of the microenvironment has been demonstrated in the selection of mutations. Specific clones harboring particular mutations may be selected due to inter-clone competition for nutrients or to the presence of an inflammatory environment. The drugs received during the chronic phase of the disease can also participate in clonal selection, which may be of particular importance in MPN patients who often require lifelong treatments. The aims of this review are to recapitulate the current knowledge of the different molecular lesions acquired in MPNs, highlight their impact on disease evolution and discuss the processes influencing their selection and expansion over time.