Clonal architecture evolution in Myeloproliferative Neoplasms: from a driver mutation to a complex heterogeneous mutational and phenotypic landscape

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.

Mapping the proteogenomic landscape enables prediction of drug response in acute myeloid leukemia

“…The dynamic nature of AML, however, is one of the main limitations of this study. For example, the bulk processing of the samples cannot account for the known clonal heterogeneity of AML 65 , 66 , 67 , 68 , 69 and differences in overall balance between stromal and leukemic cells. Rapidly evolving improvements in mass spectrometry are making it possible to analyze patient samples after enriching for specific cell types based on cell surface determinants.…”

“… 21 N/A Software and algorithms Analysis code This paper https://github.com/PNNL-CompBio/BeatAMLproteomics MASIC Maslah et al. 66 N/A WGCNA Langfelder and Horvath 72 , 73 N/A NMF Gaujoux and Seoighe 74 N/A clusterProfiler Yu et al. 75 N/A DreamAI Ma et al.…”

CXCL8 and its cognate receptors CXCR1/CXCR2 in primary myelofibrosis

“…Several genes predict worse prognosis or are associated with blast phase when mutated; amongst these are TET2 , ASXL1 , and TP53 . 11 , 12 The role of inherited variants in these genes is still not completely understood and concerns a growing area of research within MPN. 11 Germline polymorphisms may contribute or predispose a person to the development of a chronic inflammatory state, characterized by increased cytokine production or myeloid response, and thus genetic instability or even MPN development.…”

“…This hypothesis is supported by other findings, amongst which the long latency between acquiring JAK2 mutational status and development of the disease, as well as the different observed disease phenotypes and kinetics despite identical underlying mutation. 12 Currently, allogeneic stem cell transplantation remains the only potentially curative treatment option for PMF. In addition, the often higher age of patients with PMF frequently limits the ability to use full intensity conditioning.…”

Advances in Molecular Understanding of Polycythemia Vera, Essential Thrombocythemia, and Primary Myelofibrosis: Towards Precision Medicine

“…The distinction between early-stage MPNs and CHIP presents a clinical challenge, especially given the capacity of JAK2, CALR, or MPL mutations to produce MPN-like phenotypes in animal studies [55]. This underscores the need for strategies to evaluate the progression likelihood of CHIP to MPNs, enhancing patient management through potentially more intensive monitoring for those at higher risk [56].…”