Five years since the discovery of FIP1L1–PDGFRA: what we have learned about the fusion and other molecularly defined eosinophilias

Gotlib, Jason; Cools, Jan

doi:10.1038/leu.2008.287

Cited by 151 publications

(145 citation statements)

References 83 publications

(112 reference statements)

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“…In the meantime, more than 70 different BCR-ABL exchanges that confer clinical imatinib resistance have been identified in patients (Apperley, 2007). In contrast, only seven cases of FP-positive myeloproliferation with acquired imatinib resistance due to a point mutation in the PDGFRA kinase domain have been reported so far (Cools et al, 2003a;von Bubnoff et al, 2005a;Ohnishi et al, 2006;Gotlib and Cools, 2008;Simon et al, 2008;Lierman et al, 2009;Score et al, 2009). Strikingly, in six cases, either a FP/T674I (corresponding to T315I in cABL) or a D842V exchange of the FP kinase domain was identified, whereas in one case, a S601P þ L629P double mutation was detected (Simon et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…A subset of patients with primary eosinophilia fall into the WHO (World Health Organization) category of myeloid neoplasms associated with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1 (Cross and Reiter, 2008;Gotlib and Cools, 2008;Tefferi and Vardiman, 2008). Myeloid neoplasms associated with rearrangements of PDGFRA, PDGFRB and FGFR1 are considered to be very rare entities (Gotlib and Cools, 2008).…”

Section: Introductionmentioning

confidence: 99%

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The low frequency of clinical resistance to PDGFR inhibitors in myeloid neoplasms with abnormalities of PDGFRA might be related to the limited repertoire of possible PDGFRA kinase domain mutations in vitro

et al. 2010

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Myeloproliferation with prominent eosinophilia is associated with rearrangements of PDGFR-A or -B. The most common rearrangement is FIP1L1-PDGFRA (FP). The majority of patients with PDGFR-rearranged myeloproliferation respond to treatment with imatinib. In contrast to BCR-ABL-positive chronic myelogenous leukemia, only few cases of imatinib resistance and mutations of the FP kinase domain have been described so far. We hypothesized that the number of critical residues mediating imatinib resistance in FP in contrast to BCR-ABL might be limited. We performed an established systematic and comprehensive in vitro resistance screen to determine the pattern and frequency of possible TKI resistance mutations in FP. We identified 27 different FP kinase domain mutations including 25 novel variants, which attenuated response to imatinib, nilotinib or sorafenib. However, the majority of these exchanges did not confer complete inhibitor resistance. At clinically achievable drug concentrations, FP/ T674I predominated with imatinib, whereas with nilotinib and sorafenib, FP/D842V and the compound mutation T674I þ T874I became prevalent. Our results suggest that the PDGFR kinase domain contains a limited number of residues where exchanges critically interfere with binding of and inhibition by available PDGFR kinase inhibitors at achievable concentrations, which might explain the low frequency of imatinib resistance in this patient population. In addition, these findings would help to select the appropriate second-line drug in cases of imatinib-resistant disease and may be translated to other neoplasms driven by activated forms of PDGFR-A or -B.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The low frequency of clinical resistance to PDGFR inhibitors in myeloid neoplasms with abnormalities of PDGFRA might be related to the limited repertoire of possible PDGFRA kinase domain mutations in vitro

et al. 2010

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“…2,3 Yet, rare cases of secondary resistance have also been reported, with the acquisition of a T674I mutation in seven patients and a D842V mutation in one (for a recent overview, see Metzgeroth et al 4 ). 3 --5 The FIP1L1-PDGFRA-T674I mutation has limited to absent sensitivity to nilotinib and dasatinib in vitro but responds well to sorafenib.…”

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confidence: 99%

“…2 Therefore, most of the patients (95%) with an isolated 5q deletion do not fit the WHO criteria to be included in this subset of MDS, which appears to be rare. 3,4 For over 15 years, many studies have focused on defining the common deleted region of chromosome 5.…”

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confidence: 99%

Ponatinib is active against imatinib-resistant mutants of FIP1L1-PDGFRA and KIT, and against FGFR1-derived fusion kinases

et al. 2012

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“…It is noteworthy that blood hypereosinophilia (HE) is not necessarily accompanied by organ damage (criteria for Hypereosinophilic syndrome HES not fulfilled), mostly when it is detected in early stages of disease. When a persistent hypereosino-philia is demonstrated in the absence of organ involvement or an underlying disease, the provisional diagnosis of HE of uncertain significance is established [9].…”

Section: Mechanisms Of Hypereosinophiliamentioning

confidence: 99%

Eosinophilia and Hypereosinophilic Disorders – Update on Etiopathogeny, Classification and Clinical Approach

Leru

2015

Romanian Journal of Internal Medicine

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Eosinophils are innate immune leukocytes recruited in large numbers to sites of allergic inflammation and parasitic infections. Recent studies show additional pleiotropic effects of recruited eosinophils impacting immunomodulation, tissue homeostasis and repair. Pathologic conditions accompanied by blood eosinophilia are quite frequent in medical practice and may raise serious differential diagnosis problems in severe cases, that require a multidisciplinary approach. Hypereosinophilia may be reactive to other diseases or primary, representing hypereosinophilic syndromes, that are diagnosed based on clinical and laboratory criteria, according to actual international guidelines. The etiopathogenic diagnosis is difficult and delayed in many cases and clinical evolution may be severe, with multiorgan involvement and poor prognosis. Some cases remain idiopathic, despite exhaustive investigation.This paper aims to review the most recent data in the literature referring to the role of eosinophils in human pathology, diagnostic criteria and treatment strategies of hypereosinophilic syndromes, actual classification and to draw some useful recommendations in clinical practice.

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Five years since the discovery of FIP1L1–PDGFRA: what we have learned about the fusion and other molecularly defined eosinophilias

Cited by 151 publications

References 83 publications

The low frequency of clinical resistance to PDGFR inhibitors in myeloid neoplasms with abnormalities of PDGFRA might be related to the limited repertoire of possible PDGFRA kinase domain mutations in vitro

The low frequency of clinical resistance to PDGFR inhibitors in myeloid neoplasms with abnormalities of PDGFRA might be related to the limited repertoire of possible PDGFRA kinase domain mutations in vitro

Ponatinib is active against imatinib-resistant mutants of FIP1L1-PDGFRA and KIT, and against FGFR1-derived fusion kinases

Eosinophilia and Hypereosinophilic Disorders – Update on Etiopathogeny, Classification and Clinical Approach

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