Molecular Pathogenesis and Treatment Perspectives for Hypereosinophilia and Hypereosinophilic Syndromes

Abstract

Hypereosinophilia (HE) is a heterogeneous condition with a persistent elevated eosinophil count of >350/mm³, which is reported in various (inflammatory, allergic, infectious, or neoplastic) diseases with distinct pathophysiological pathways. HE may be associated with tissue or organ damage and, in this case, the disorder is classified as hypereosinophilic syndrome (HES). Different studies have allowed for the discovery of two major pathogenetic variants known as myeloid or lymphocytic HES. With the advent of molecular genetic analyses, such as T-cell receptor gene rearrangement assays and Next Generation Sequencing, it is possible to better characterize these syndromes and establish which patients will benefit from pharmacological targeted therapy. In this review, we highlight the molecular alterations that are involved in the pathogenesis of eosinophil disorders and revise possible therapeutic approaches, either implemented in clinical practice or currently under investigation in clinical trials.

Keywords: NGS; PDGFRα and PDGFRβ fusions; TCR rearrangements; hypereosinophilia; hypereosinophilic syndromes.

Figure 1

Hypereosinophilic syndromes (HES) classification.

Figure 2

Schematic representation of platelet-derived growth factor receptor alpha (PDGFRα) and PDGFRβ fusion rearrangements. (a) FIP1L1-PDGFRα; (b) breakpoint cluster region-PDGFRα (BCR-PDGFRα); and, (c) ETV6-PDGFRβ. The arrows indicate the position of breakpoints of PDGFRs. BCR = breakpoint cluster region; CC = Coiled-Coil; ETS = (Erythroblast Transformation Specific) DNA-binding domain; ETV = ETS Variant Transcription Factor 1; FIP1L1 = Fip1-like1; GEF = Guanine Nucleotide Exchange Factor; HLH = Helix-Loop-Helix oligomerization domain; NLS = Nuclear Localization Signal; PDGFR = Platelet-Derived Growth Factor Receptor; RacGAP = COOH-terminal GTPase Activating Protein (GAP) domain; TM = Transmembrane; TK = Tyrosine Kinase.

Figure 3

Schematic representation of FGFR1 fusion rearrangements. (a) ZMYM2-FGFR1; (b) BCR-FGFR1; (c) CNTRL-FGFR1. The arrows indicate the position of breakpoints of FGFR1. BCR = breakpoint cluster region; CC = Coiled–Coil; CNTRL = Centriolin; FGFR1 = fibroblast growth factor receptor 1; GEF = Guanine Nucleotide Exchange Factor; RacGAP = COOH-terminal GTPase Activating Protein (GAP) domain; TK = Tyrosine Kinase; LRR = Leucine-Rich Repeat; ZNF = Zing Finger; ZMYM2 = Zinc finger MYM-type protein 2.

Figure 4

Schematic representation of JAK2 fusion rearrangements. (a) PCM1-JAK2; (b) BCR-JAK2; and, (c) ETV6-JAK2. The arrows indicate the position of breakpoints of JAK2. BCR = breakpoint cluster region; CC = Coiled Coil; GEF = Guanine Nucleotide Exchange Factor; ETS = (Erythroblast Transformation Specific) DNA-binding domain; HLH = Helix-Loop-Helix oligomerization domain; FERM = 4.1 ezrin, radixin and moesin domain; JAK2 = janus kinase 2; PCM1 = Pericentriolar Material 1; PK = Pseudo kinase domain; RacGAP = COOH-terminal GTPase Activating Protein (GAP) domain; SH2 = Src-homology-2 domain; TK = Tyrosine Kinase.

Figure 5

Working model depicting the mechanism of action of pharmacological agents used in hypereosinophilia disorders.Alemtuzumab = anti-CD52 monoclonal antibody; Benralizumab = anti-IL5-R monoclonal antibody; Dexpramipexole, Hydroxyurea and IFNα = cytotoxic agents; Imatinib and Nilotinib = PDGFRs inhibitors; Pegatinib = FGFR1 inhibitor; Mepolizumab, Reslizumab and 610 = recombinant anti-IL5 humanized monoclonal antibody; Omalizumab = anti-IgE monoclonal antibody; Prednisolone = corticosteroid; Ruxolitinib = Jak2 inhibitor; Sorafenib = PDGFRα and FLT3 inhibitor; Venetoclax in combination with Azacitidine and Pevonedistat = chemotherapy regimens.