FIP1L1/PDGFR alpha-associated systemic mastocytosis

Abstract

Since the identification of the FIP1L1/PDGFRA fusion gene as a pathogenic cause of the hypereosinophilic syndrome (HES), the importance of the molecular classification of HES leading to the diagnosis of chronic eosinophilic leukemia (CEL) has been recognized. As a result, a new category, 'myeloid and lymphoid neoplasm with eosinophilia and abnormalities in PDGFRA, PDGFRB or FGFR1', has recently been added to the new WHO criteria for myeloid neoplasms. FIP1L1/PDGFR alpha-positive disorders are characterized by clonal hypereosinophilia, multiple organ dysfunctions due to eosinophil infiltration, systemic mastocytosis (SM) and a dramatic response to treatment with imatinib mesylate. A murine HES/CEL model by the introduction of FIP1L1/PDGFR alpha and IL-5 overexpression also shows SM, representing patients with FIP1L1/PDGFR alpha-positive HES/CEL/SM. The murine model and the in vitro development system of FIP1L1/PDGFR alpha-positive mast cells revealed the interaction between FIP1L1/PDGFR alpha, IL-5 and stem cell factor in the development of HES/CEL/SM. Current findings of FIP1L1/PDGFR alpha-positive HES/CEL are reviewed focusing on aberrant mast cell development leading to SM.

Fig. 1

Intracellular signaling of FIP1L1/PDGFRα+ (F/P) cells. FIP1L1/PDGFRα+ (F/P) primary mouse eosinophils express up-regulated IL-5Rα and FIP1L1/PDGFRα activates the JAK2/STAT5 pathway. The CCR3/ERK1/2 signaling pathway may be amplified by FIP1L1/PDGFRα expression [25]. Up-regulated expressions of α₄ integrin and Siglec-F were observed in FIP1L1/PDGFRα+murine eosinophils [8]. FIP1L1/PDGFRα synergizes with SCF stimulation via c-kit to activate Akt signaling in mouse mast cells. Eosinophils and mast cells also express c-kit and IL-5Rα, respectively.

Fig. 2

FIP1L1/PDGFRα in conjunction with SCF and IL-5 promote leukemic hematopoiesis and eosinophil and mast cell (MC) development. FIP1L1/PDGFRα may occur in hematopoietic stem cells or early progenitor cells resulting in the expression of FIP1L1/PDGFRα in most hematopoietic cells. Progenitors including earlier and mature eosinophils and MCs express c-kit. In contrast, IL-5Rα expression has been observed on eosinophil progenitor (EoP), MC progenitor (MCP) and mature eosinophils and MCs. FIP1L1/PDGFRα enhances SCF/c-kit signaling by sharing downstream signaling and up-regulates IL-5Rα expression facilitating its intracellular signaling. There is significant crosstalk between eosinophils and MCs. These findings imply that FIP1L1/ PDGFRα in collaboration with SCF may affect leukemic myeloproliferation, and synergistically with IL-5 expand and activate MC and eosinophil lineages. ST-HSC = Short-term HSC; CMP = common myeloid progenitor; GMP = granulocyte-macrophage progenitor.