Myeloid and Lymphoid Neoplasms with Eosinophilia and Abnormalities of PDGFRA, PDGFRB, FGFR1, or t(8;9)(p22;p24.1);PCM1-JAK2

Chaffin, Joanna; Savage, Natasha M.

doi:10.1007/978-3-319-62146-3_16

Cited by 3 publications

(3 citation statements)

References 128 publications

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“…In contrast, the genetic characteristic of PDGFRA gene aberration, as well as the high diversity of these genetic abnormalities, make them indiscernible by conventional methods. As a consequence, most of the eosinophilia patients with PDGFRA gene abnormality are erroneously regarded as a hypereosinophilic syndrome with unknown etiology 6,22 …”

Section: Discussionmentioning

confidence: 99%

Phosflow assessment of PDGFRA phosphorylation state: A guide for tyrosine kinase inhibitor targeted therapy in hypereosinophilia patients

et al. 2021

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Clonal eosinophilia is a hematologic disorder caused by translocation in growth factor receptor (GFR) genes. Despite the identified molecular mechanisms underlying clonal hypereosinophilia, the distinction between clonal and reactive eosinophilia has remained challenging due to the diversity of partner genes for translocated GFRs. This study aimed to examine the feasibility of phosphoflow cytometry in the diagnosis of clonal hypereosinophilia through evaluating the level of platelet‐derived growth factor receptor alpha (PDGFRA) phosphorylation and its correlation with PDGFRA genetic aberration. Blood samples were collected from 45 hypereosinophilia patients and 10 healthy controls. Using phosphoflow cytometry method, the phosphorylation state of PDGFRA was assessed. The specificity of phosflow results was confirmed by western blotting and eventually compared with qRT‐PCR expression analysis of 3′‐region of PDGFRA. To detect the genetic aberration of PDGFRA, 5′‐rapid amplification of cDNA ends (5′‐RACE) was performed. Phosflow analysis illustrated that 9 of 45 hypereosinophilic patients had higher level of PDGFRA phosphorylation while sequence analysis of 5′‐RACE‐PCR fragments confirmed that in seven cases of them, there was a PDGFRA‐FIP1L1 fusion. We also verified that two of nine patients with hyperposphorylated PDGFRA hold ETV6‐PDGFRA and STRN‐PDGFRA rearrangements. Importantly, nine cases also had significantly higher levels of PDGFRA mRNA expression when compared with healthy controls, and cases with no PDGFRA rearrangement. These findings highlight a robust correlation between hyperphosphorylation state of PDGFRA and aberrant PDGFRA gene fusions. This implicates phosflow as an efficient and reliable technique raising an intriguing possibility that it could replace other genomic and cDNA‐amplification‐based diagnostic approaches with limited effectiveness.

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Section: Discussionmentioning

confidence: 99%

Phosflow assessment of PDGFRA phosphorylation state: A guide for tyrosine kinase inhibitor targeted therapy in hypereosinophilia patients

et al. 2021

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“…The first PDGFRA genetic alteration was reported by Todd and Gary Gilliland, in 1994 and was identified in chronic myelomonocytic leukemia (6,11). Later, many other PDGFRA mutations were described until now (12,13).…”

Section: Introductionmentioning

confidence: 99%

“…However, in BCR-ABL independent pathways, the BCR-ABL tyrosine kinase was not only inhibited by imatinib but other alternative pathways may have become activated due to other key enzymes responsible for cell proliferation and immobilisation (5). Involvement of other tyrosine kinases that can also be inhibited by imatinib such as platelet derived growth factor receptor alpha (PDGFRA) can also be a potential determinant involved in imatinib resistance in CML patients (6).…”

Section: Introductionmentioning

confidence: 99%

Application of HRM Analysis in Detection of PDGFRA Exon 10 Polymorphism in CML Patients with Imatinib Resistance

Rashid¹,

Sulong²,

Azlan³

et al. 2022

MJMHS

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Introduction: Imatinib mesylate has been widely used as a standard treatment for chronic myeloid leukemia (CML). It acts as a selective competitive inhibitor of the BCR-ABL tyrosine kinase. Despite the excellent efficacy on CML treatment, some patients developed resistance to the treatment. Mutation in the PDGFRA may be one of the factors involved in the mechanism of resistance that affects the response to imatinib. The mutational status of PDGFRA is highly relevant for prognosis and treatment prediction in CML patients. Thus, this study is intended to establish and validate a High Resolution Melting (HRM) analysis for PDGFRA exon 10 c.1432 T>C polymorphism in CML patients. Methods: High resolution melting (HRM) analysis was used to identify the c.1432 T > C polymorphism in PDGFRA exon 10 (n =86; response = 43; resistance = 43). The results from HRM analysis were compared and validated with Sanger sequencing. The association between the polymorphism and treatment response was assessed by statistical analysis using binomial logistic regression analysis. Results: HRM analyses showed two different melt curves. One curve followed the shape of the reference, homozygous wild type (TT) and the other curve showed a different melting profile than the reference with the TC genotype (heterozygous variant). The results revealed that heterozygous variant (TC) genotype showed a high risk of acquiring resistance with an OR of 3.795; 95% CI: 1.502-9.591, with a statistically significant association, p = 0.005. HRM analysis also showed 100% sensitivity and specificity in the detection of PDGFRA exon 10. Conclusion: The HRM analysis of PDGFRA exon 10 c.1432 T>C was successfully established. The exon 10 c.1432 T>C polymorphism shows a higher risk for the development of resistance toward imatinib treatment.

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Biological Markers of Myeloproliferative Neoplasms in Children, Adolescents and Young Adults

Ozygała,

Rokosz-Mierzwa,

Widz

et al. 2024

Cancers

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Myeloproliferative neoplasms (MPNs) are clonal hematopoietic cancers characterized by hyperproliferation of the myeloid lineages. These clonal marrow disorders are extremely rare in pediatric patients. MPN is reported to occur 100 times more frequently in adults, and thus research is primarily focused on this patient group. At present, modern diagnostic techniques, primarily genetic, facilitate the identification of the biology of these diseases. The key genes are JAK2, MPL, and CALR, namely, driver mutations, which are present in approximately 90% of patients with suspected MPN. Moreover, there are more than 20 other mutations that affect the development of these hematological malignancies, as evidenced by a review of the literature. The pathogenic mechanism of MPNs is characterized by the dysregulation of the JAK/STAT signaling pathway (JAK2, MPL, CALR), DNA methylation (TET2, DNMT3A, IDH1/2), chromatin structure (ASXL1, EZH2), and splicing (SF3B1, U2AF2, SRSF2). Although rare, myeloproliferative neoplasms can involve young patients and pose unique challenges for clinicians in diagnosis and therapy. The paper aims to review the biological markers of MPNs in pediatric populations—a particular group of patients that has been poorly studied due to the low frequency of MPN diagnosis.

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Myeloid and Lymphoid Neoplasms with Eosinophilia and Abnormalities of PDGFRA, PDGFRB, FGFR1, or t(8;9)(p22;p24.1);PCM1-JAK2

Cited by 3 publications

References 128 publications

Phosflow assessment of PDGFRA phosphorylation state: A guide for tyrosine kinase inhibitor targeted therapy in hypereosinophilia patients

Phosflow assessment of PDGFRA phosphorylation state: A guide for tyrosine kinase inhibitor targeted therapy in hypereosinophilia patients

Application of HRM Analysis in Detection of PDGFRA Exon 10 Polymorphism in CML Patients with Imatinib Resistance

Biological Markers of Myeloproliferative Neoplasms in Children, Adolescents and Young Adults

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