An interstitial deletion del(4)(q12q12) generating a FIP1L1-PDGFRA fusion gene is observed in diverse eosinophilia-associated hematologic disorders like hyperseosinophilic syndrome (HES), systemic mastocytosis (SM) and chronic eosinophilic leukemia (CEL). The updated WHO classification distinguishes these myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1 as chronic eosinophilic leukemia (CEL) not otherwise specified (NOS); lymphocyte-variant hypereosinophilia and idiopathic hypereosinophilic syndrome (HES) (Gleich and Leiferman, 2009; Gotlib, 2014). Occasionally, the FIP1L1-PDGFRA fusion can be identified in patients with acute myeloid leukemia or B-cell or T-cell acute lymphoblastic leukemia or lymphoblastic lymphoma and sporadically in myeloid sarcoma (Metzgeroth et al., 2007; Tang et al., 2012).

FIP1L1-PDGFRA rearrangement has been found in a variety of cell lineages (neutrophils, monocytes, eosinophils, CD34+ cells, mast cells and even lymphoid) consistent with an origin in an hematopoietic stem cells or early progenitors progenitor (Gotlib and Cools, 2008).

The cause of FIP1L1-PDGFRA associated hypereosinophilic syndrome is unknown as well as its association with predominantly male sex.

FIP1L1-PDGFRA (+) eosinophilias are considered to be rare entities; however the incidence rates for molecularly defined eosinophilic disorders are not known. Data support a FIP1L1-PDGFRA fusion incidence of approximately 10-20% among patients presenting with idiopathic hypereosinophilia (Gotlib and Cools, 2008). However, in unselected patients with eosinophilia only 3% of were found to carry the FIP1L1-PDGFRA fusion (Pardanani et al., 2004; Pardanani et al., 2006).

Characteristic feature of PDGFRA-associated disorders is eosinophil overproduction in the bone marrow resulting in increased blood eosinophils. Marked and sustained eosinophilia eventually leads to eosinophilic infiltration and functional damage of peripheral organs, most commonly the heart, skin, lungs, or nervous system. Patients often present with hepatomegaly or splenomegaly hypercellular bone marrows with myelofibrosis, increased number of neutrophils and/or mast cells. Serum B12 and tryptase levels may be significantly elevated (Vandenberghe et al., 2004; Gleich and Leiferman, 2009).

FIP1L1-PDGFRA associated hypereosinophilic disorders are sensitive to treatments with tyrosine kinase inhibitors such as imatinib mesylate (imatinib). Imatinib is the first-line therapy for patients with abnormalities of PDGFRA; however chronic eosinophilic leukemia with FIP1L1-PDGFRA is likely to be responsive also to dasatinib, nilotinib, sorafenib and midostaurin (PKC412) (Lierman et al., 2009).

Patients with hypereosinophilic syndrome historically carried a poor prognosis before the successful therapeutic application of tyrosine kinase inhibitors. Targeted therapy has dramatically changed the prognosis of patients carrying the FIP1L1-PDGFRA fusion which show an excellent response to low-dose imatinib. Treatment with low-dose imatinib (100 mg/d) produced complete and durable responses with normalization of eosinophilia. Importantly, these remissions appear to be durable with continued imatinib therapy in a high proportion of patients (Barraco et al., 2014). Acquired resistance is exceedingly rare; the T674I mutation in the ATP-binding region of PDGFRA (mutation of the threonine at position 674) is the most common. Interestingly, the T674I mutation that is analogous to the T315I mutation of BCR-ABL1 in chronic myeloid leukemia also confers imatinib resistance (Cools et al., 2003; Jain et al., 2013). For refractory disease, interferon-a may be a therapeutic option.

The cryptic interstitial deletion on chromosome band 4q12 leading to FIP1L1-PDGFRA fusion is quite unique as it is generated by a cryptic chromosomal deletion, rather than a translocation (Gotlib and Cools, 2008).

Because FIP1L1-PDGFRA is generated by a cryptic deletion at 4q12 that is only 800 kb in size, it remains undetected with standard cytogenetics. Therefore; most of the patients with the fusion have an apparently normal karyotype. Occasional patients have had a chromosomal rearrangement with a 4q12 breakpoint, such as t(1;4)(q44;q12), which ultimately led to the identification of the fusion gene or t(4;10)(q12;p11) (Cools et al., 2003; Gotlib et al., 2004).

One of the best techniques to detect the presence of the FIP1L1-PDGFRA fusion gene is using triple-color FISH probes hybridizing to the region between the FIP1L1 and PDGFRA genes incorporating the CHIC2 (cysteine-rich hydrophobic domain 2) gene. A more sensitive technique is the use of reverse-transcription polymerase chain reaction (RT-PCR) (La Starza et al., 2005) or quantitative RT-PCR methods, used for monitoring therapy response to tyrosine kinase inhibitors.

A few other variant PDGFRA fusion genes have been described: t(4;22)(q12;q11)/BCR-PDGFRA, t(2;4)(p24;q12)/STRN-PDGFRA, ins(9;4)(q33;q12q25)/CDK5RAP2-PDGFRA, complex karyotype/KIF5B-PDGFRA and t(4;12)(q12;p13)/ETV6-PDGFRA (Gleich and Leiferman, 2009). The involvement of FIP1L1 was described in a t(4;17)(q12;q21) with FIP1L1/RARA fusion in a patient with juvenile myelomonocytic leukemia (Shah et al., 2014).

In-frame fusion of the 5 part of FIP1L1 to the 3 part of PDGFRA.
The FIP1L1-PDGFRA protein is made by the first twelve exons of FIP1L1 and from truncated exon 12 (containing the last 17 amino acids) to exon 23 of PDGFRA. The FIP1L1-PDGFRA fusion protein is a constitutively activated tyrosine kinase that joins the first 233 amino acids of FIP1L1 to the last 523 amino acids of PDGFRA (Gotlib and Cools, 2008).

5FIP1L1-3PDGFRA; no reciprocal PDGFRA-FIP1L1 fusion gene can be detected as the fusion is the consequence of an interstitial deletion and not a reciprocal translocation. As the normal splice site at 5 part of exon 12 of PDGFRA is deleted, cryptic splice sites in FIP1L1 introns or within exon 12 of PDGFRA are used to generate in-frame FIP1L1-PDGFRA fusions (Gotlib and Cools, 2008).

An interstitial deletion on chromosome 4q12 site brings the normally distant PDGFRA and FIP1L1 genes into proximity generating a hybrid FIP1L1-PDGFRA gene. In the translated protein, the juxtamembrane domain of PDGFRA that is known to serve an autoinhibitory function is truncated and became under control of the ubiquitous FIP1L1 promoter resulting in its constitutive kinase activation. Dysregulated tyrosine kinase activity leads to proliferation of multiple myeloid lineages via activation of several pathways. The STAT1/3 and STAT5 (signal transducers and activators of transcription) transcriptional factors appear to be activated either directly or via interaction with JAK (Janus activated kinase) pathways. However, the exact mechanism, by which FIP1L1-PDGFR affects the development of HES/CEL and why preferentially affects eosinophils remains unclear. Mouse models of FIP1L1-PDGFRA induced disease revealed that FIP1L1-PDGFRA expression induce a myeloproliferative phenotype without eosinophilia. Therefore, it is likely that FIP1L1-PDGFRA expression alone is not sufficient to cause eosinophilia and additional processes such as cooperation with nuclear factor-kB and IL-5 signaling are required in differentiation towards the eosinophil lineage (Yamada et al., 2006; Montano-Almendras et al., 2012).

FIP1L1/PDGFRA FIP1L1 (4q12) PDGFRA (4q12) TIC