While the FIP1L1/PDGFRA fusion gene is mainly known for its association with hypereosinophilia, this abnormal gene was also identified in patients with systemic mastocytosis. In this issue of Blood, Yamada and colleagues' study of an elegant mouse model for FIP1L1/PDGFRA–induced eosinophilia reveals that FIP1L1/PDGFRα synergizes with activated Kit, the receptor for stem cell factor, to promote mast cell development, activation, and survival.
Five years ago, the FIP1L1/PDGFRA fusion gene was identified in patients with hypereosinophilic syndrome (HES). Since then, many other studies have confirmed the presence of the FIP1L1/PDGFRA fusion gene in a significant fraction of hypereosinophilia patients and have shown that these patients have excellent responses to imatinib treatment.1,2 Given the documented clonality of the disease in HES patients, the preferred nomenclature for this disease is FIP1L1/PDGFRA chronic eosinophilic leukemia (CEL). Eosinophilia is also frequently observed in systemic mastocytosis, and up to half of these cases are also positive for the FIP1L1/PDGFRA fusion gene.3 It is currently undecided whether to call this disease systemic mastocytosis with eosinophilia, or rather FIP1L1/PDGFRA–positive CEL,3,4 illustrating the close relationship between both FIP1L1/PDGFRA–positive diseases.
Infiltration of mast cells in the small intestine of FIP1L1/PDGER α expressing mice versus FN “AND” replaced with “vs.” control mice. See the complete figure in the article beginning on page 2500.
On the other hand, there is no doubt about the specific association of the FIP1L1/PDGFRA gene with eosinophilia. Attempts to model this in mice have, however, been difficult. Simple expression of FIP1L1/PDGFRA in the bone marrow cells of mice using the classic bone marrow transplantation model results in the generation of a myeloproliferative disease without striking eosinophilia.5 Yamada et al modified this mouse model and showed that FIP1L1/PDGFRA expression, when combined with overexpression of interleukin-5, was able to recapitulate typical features of HES/CEL, including hypereosinophilia and tissue infiltration of eosinophils.6 In addition to this study, recent work from the group of Nicholas C. P. Cross suggests that variations in IL5RA expression are linked to constitutional IL5RA genotype and severity of FIP1L1/PDGFRA–positive CEL.7 Together, these data may suggest that FIP1L1/PDGFRA alone is not sufficient to cause CEL, at least in mice, and that other cooperating factors are required and may be additional targets for therapy.
In this issue of Blood, Yamada et al extend their previous findings on the FIP1L1/PDGFRα/interleukin-5 mouse model and present a detailed analysis of the effect of FIP1L1/PDGFRα on mast cell biology. Their analyses reveal that FIP1L1/PDGFRα synergizes with stem cell factor (SCF) stimulation via Kit to promote mast cell development, activation, and survival. SCF is a key factor for the development of mast cells from bone marrow precursors but normally requires cofactors, such as IL-3 and IL-4. The work by Yamada et al suggests that signaling by the activated tyrosine kinase FIP1L1/PDGFRα may replace the need for these cofactors. They also nicely demonstrate that interference with activation of Kit by administration of an anti-Kit antibody diminished infiltrations of mast cells in the intestine and spleen. Since KIT is potently inhibited by imatinib, the translation of these results toward clinical practice may already have been accomplished, as this kinase inhibitor is the standard treatment for FIP1L1/PDGFRA–positive disease. It remains to be determined whether polymorphisms that influence the expression levels of the KIT or SCF genes may determine phenotypic differences within the group of FIP1L1/PDGFRA–positive diseases.
I have just been diagnosed as being FIP1L1-PDGFRA positive but they haven't stated categorically whether it is HES with FIP1L1-PDGFRA or CEL. I'm waiting to see the haemotologist in a couple of days. I have a high mast cell tryptase level so the presentation is more sytemic mastocytosis/HES related and my internal organ involvement is, thus far, very minimal.
This is usefulpaper as it provides me with more detail on HES/CEL. Thaks very much
I'm sorry to hear about your diagnosis. Scary day indeed.
From what I know, once they've proven that it is clonal, which they have in your case, it is CEL Gleevec works excellent for the mutation. I am currently on 400mg daily. I take it before bed at night. Minimal side effects.
You can see my other posts in this subforum for more information. I am 2 years+ post diagnosis and am living life normally.
Please keep in touch since there are so few of out out there. I've been told that only a few hundred cases a year are diagnosed with the mutation.
Thanks for your reply. Scarey ... Yes that's an understatement!! I live in the UK and there is so little information for patients due to the rarity. I've read up on gleevec so expect this to be the drug of choice- it was in the diagnosis recommendations.
I'll let you know how I get on with haematology.
Sorry, Its been a while I know, been quite an uphill struggle really.
I too have FIP1L1-PDFGRa+ CEL; there are not many of around! I too would be happy to share my experiences. I have been on Gleevec since diagnosis in May 2012 initially started at 100mg, but upped to 200mg in Feb 13 due to the fact that my mast cell tryptase level began to climb again (it was 145 at diagnosis, and is now 11, which is back in the normal range. My eos count fell to zero after a month on treatment. I'm waiting on my latest bone marrow biopsy to find out if there is any trace of the fusion gene at this point.
I have suffered with fatigue and rhinitis and congestion, which just does not seem to go away. It was one of the symptoms, but I have just not been able to get it under control. In fact it is worse now than before diagnosis, but I am wondering if my autoimmune systems is no just more active? We have an elderly dog who seems to shed hair. I am wondering actually if it is that which is setting it off (dog dander), rather than be a function of the disease.
Anyway, blood tests tomorrow, and follow up next Tuesday - fingers crossed!
Hope you are well - all the best,