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A Unique Rearrangement of PDGFRα and ETV6 in a new t(4;12;6) in a Patient with Acute Myeloid Leukemia (M4) Progressed from Chronic Myelomonocytic Leukemia.

ABSTRACT: Objectives: Platelet derived growth factor receptor alpha (PDGFRα), which, encodes cell surface tyrosine kinase receptors for the platelet derived growth factor family undergoes different types of rearrangements creating fusion genes in myeloid neoplasms. A cryptic deletion at 4q12 creating a fusion gene FIP1L1/ PDGFRα is the most frequent change and is associated with malignant hypereosinophilia that can lead to organ damage. The other infrequent, but consistent change involving PDGFRα seen in acute myeloid leukemia (AML) and in other myeloproliferative neoplasms with eosinophilia is a t(4;12)(q12;p13) that creates a fusion gene with ETV6. This change activates ETV6 via the tyrosine kinase domain of the PDGFRα. In this report we cytogenetically characterized a new t(4;12;6) translocation which developed during transformation to AML in a patient with chronic myelomonocytic leukemia (CMML). Methods: The patient, a 70 year old male diagnosed with CMML; leukemic cells were JAK2- and ABL1/BCR/ABL1 negative and the karyotype was normal. Eight months from diagnosis the disease progressed to AML and concurrently had a low-grade follicular lymphoma. Standard G-band karyotype analysis and FISH analysis was performed to characterize the translocation to develop appropriate therapy based on genetic findings. Results: The patient was initially treated with hydroxyurea and allopurinoal, later it was changed to Azacytidine for CMML. At the time of transformation to AML, the BM karyotype showed a t(4;12;6)( q12;p13;p21.3). FISH with a tricolor 4q12 probe and ETV6 showed fusion between PDGFRα and ETV6.Concurentllty the patient had a low-grade non-Hodgkin lymphoma. Therefore the treatment was changed to imatinib for AML and high dose methylprednisolone and rituximab for lymphoma. Due to continued progression of the disease treatment was changed again to 5+2 (cytarabine 100mg/m2/day) for 5 days and idarubicin (13mg/m2/day for 2 days). Disease progressed further and the patient expired 11 months from diagnosis. Conclusion: This is the first report of development of a variant t(4;12;6) and fusion PDGFRα/ETV6 fusion that developed during transition from CMML to AML. Despite PDGFRα/ETV6 fusion the patient did not respond to imatinib.

ORGANISM(S): Homo sapiens

PROVIDER: GSE80263 | GEO | 2016/04/15

SECONDARY ACCESSION(S): PRJNA318521

REPOSITORIES: GEO

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Project description:ETV6::FRK is a rare kinase-related fusion gene which was identified only in AML but not in ALL. Herein, we firstly identified ETV6::FRK fusion gene in a patient with pediatric B-ALL. Because FRK is Src family tyrosine kinase, we performed functional analysis of ETV6::FRK to establish molecular targeting therapy. Our case with B-ALL was refractory to conventional chemotherapy and received allogeneic bone marrow transplantation following administration of blinatumomab. Cytogenetic analysis demonstrated 46,XY,t(6;12)(q21;p13) and target capture mRNA sequencing revealed ETV6::FRK. Ba/F3 cells expressing ETV6::FRK generated by retroviral transduction (Ba/F3-ETV6::FRK) and analyzed for IL-3 independent growth. Gene expression analysis using whole transcriptome sequencing and gene set enrichment analysis (GSEA) was performed for comprehensive analysis of gene expression profile related to ETV6::FRK. It was also analyzed whether dasatinib, which is Src-kinase inhibitor, suppressed the growth of Ba/F3-ETV6::FRK in vitro and in vivo. Ba/F3-ETV6::FRK proliferated without IL-3, suggesting ETV6::FRK had proliferation activity. Western blot revealed that constitutive phosphorylation of tyrosine residue of ETV6::FRK and STAT3/STAT5, suggesting constitutive activation of FRK-STAT3/STAT5 pathway. GSEA of oncogenic gene sets (C6) from the GSEA Molecular Signatures Database revealed that, compared with control cells, Ba/F3-ETV6::FRK cells were enriched for up-regulation of SNF5 target genes and down-regulation of RB target genes involved in cell cycle regulation. In vitro killing assay showed that dasatinib killed efficiently Ba/F3-ETV6::FRK. Dasatinib also suppressed the growth of Ba/F3-ETV6::FRK in vivo and extended the survival time of the xenografted NSG mice. These findings suggest that activation of FRK-STAT3/STAT5 pathway contributes aberrant growth promotion of Ba/F3-ETV6::FRK. Our study demonstrated that dasatinib might be effective for the patient with B-ALL harboring ETV6::FRK.

Dataset Information

A Unique Rearrangement of PDGFRα and ETV6 in a new t(4;12;6) in a Patient with Acute Myeloid Leukemia (M4) Progressed from Chronic Myelomonocytic Leukemia.

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