Novel Molecular Insights into Leukemic Evolution of Myeloproliferative Neoplasms: A Single Cell Perspective

Abstract

Myeloproliferative neoplasms (MPNs) are clonal disorders originated by the serial acquisition of somatic mutations in hematopoietic stem/progenitor cells. The major clinical entities are represented by polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), that are caused by driver mutations affecting JAK2, MPL or CALR. Disease progression is related to molecular and clonal evolution. PV and ET can progress to secondary myelofibrosis (sMF) but can also evolve to secondary acute myeloid leukemia (sAML). PMF is associated with the highest frequency of leukemic transformation, which represents the main cause of death. sAML is associated with a dismal prognosis and clinical features that differ from those of de novo AML. The molecular landscape distinguishes sAML from de novo AML, since the most frequent hits involve TP53, epigenetic regulators, spliceosome modulators or signal transduction genes. Single cell genomic studies provide novel and accurate information about clonal architecture and mutation acquisition order, allowing the reconstruction of clonal dynamics and molecular events that accompany leukemic transformation. In this review, we examine our current understanding of the genomic heterogeneity in MPNs and how it affects disease progression and leukemic transformation. We focus on molecular events elicited by somatic mutations acquisition and discuss the emerging findings coming from single cell studies.

Keywords: leukemic transformation; molecular landscape; molecular pathogenesis; single cell genomics; single cell transcriptomics myeloproliferative neoplasms.

Figure 2

Molecular landscape in MPN-CP and MPN-BP. Panel (A) reports the frequency of patients harboring one of the three driver mutations considering PMF, PV and ET separately. In Panel (B) the proportion of patients harboring 0, 1, 2 or more than or equal to 3 variants other than the driver mutations is represented. Histogram in Panel (C) compares the frequency of patients harboring each mutation in MPN-CP and MPN-BP. Data adapted from: Tefferi et al., 2016 [21], Tefferi et al., 2016 [22], Grinfeld et al., 2018 [24], Venton et al., 2018 [25], Lasho et al., 2018 [26] and McNamara et al., 2018 [27].

Figure 1

Routes of disease progression and evolution in MPNs. Owing to overlapping clinical features, different disorders belonging to the MPN family can evolve into one another. State transitions can be defined based on the degree of bone marrow fibrosis and/or the frequency of blasts in peripheral blood and bone marrow. Disease evolution is associated with increasing molecular heterogeneity. Percentages represent the observed frequency of disease progression and evolution in MPN patients. Shades of red represents disease aggressiveness. ET: Essential Thrombocythemia; PV: Polycythemia Vera; pre-PMF: pre-fibrotic Primary Myelofibrosis; PET-MF: post-ET Myelofibrosis; PPV-MF: post-PV Myelofibrosis; sAML: secondary Acute Myeloid Leukemia; MPN: Myeloprolifertive Neoplasm; MPN-CP: MPN chronic phase; MPN-AP: MPN accelerated phase; MPN-BP: MPN blast phase.

Figure 3

Molecular events responsible to MPN onset and evolution. This image summarizes the molecular processes and pathways involved in MPN onset and leukemic evolution described in the main text. Abbreviations: JAK2: Janus Kinase 2; CALR: Calreticulin; TPO-R: Thrombopoietin Receptor; STAT: Signal Transducer and Transcription Activator; PRC2: Polycomb Repressive Complex 2; ASXL1: Additional Sex Combs Like 1; EZH2: Enhancer of Zeste Homolog 2; EED: Polycomb protein EED; SUZ12: Polycomb protein SUZ12; RBBP4/7: Histone-binding protein RBBP4/7; Ac: Acetylation; Me3: three-methylation; H3K27: Histone 3 Lysin 27; DNMT3A: DNA methyltransferase 3 α; TET2: Ten-Eleven-Translocation 2; IDH1/2: Isocitrate Dehydrogenases 1/2; ISO: Isocitrato; α-KG: α-ketoglutarate; 2-HG: 2-Hidroxyglutarate; p53: Tumor Protein 53; SRSF2: Serine/Arginine Rich Splicing Factor 2; SF3B1: Splicing factor 3B subunit 1; U2AF1: Splicing factor U2AF 35 kDa subunit; U2AF1: U2 small nuclear ribonucleoprotein auxiliary factor 35 kDa subunit-related protein 2; RUNX1: Runt-related transcription factor 1; SETBP1: SET binding protein 1; FLT3: FMS-like tyrosine kinase 3; SHP2: SH2 containing protein tyrosine phosphatase-2; Ras: Rat sarcoma virus; Raf: RAF proto-oncogene serine/threonine-protein kinase; MEK: Mitogen-activated protein kinase kinase; ERK: extracellular signal-regulated kinase; STAG2: Stromal Antigen 2; NPM1: Nucleophosmin; PU.1: Transcription factor PU.1. Created with BioRender.com.

Figure 4

Clonal architecture and dynamics. Figure represents the possible clonal structures observed in MPN patients who evolved to sAML as reconstructed according to single cell genomics studies. Panel (A) shows the possible patterns of clonal architecture, while in pale (B) are reported fish plots representing the possible clonal dynamics.