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![Bone marrow: (a, b) Low magnification of the bone marrow aspirate showing myeloid hyperplasia and hypolobated megakaryocytes; (c, d) cytogenetic analysis showed a 46,XY,t(8;22)(p11;q11)[19]/46,XY[1]. Fluorescence in situ hybridization showed the split of one of the two fusion signals indicating a chromosome breakage in the FGFR1 locus; (e) low magnification of the bone marrow biopsy showing hypercellular marrow (hematoxylin and eosin); (f) reticulin stain demonstrating a mild grade of fibrosis.](publication/329459581/figure/fig5/AS:1086449441083407@1636041140957/Bone-marrow-a-b-Low-magnification-of-the-bone-marrow-aspirate-showing-myeloid.jpg)
Bone marrow: (a, b) Low magnification of the bone marrow aspirate showing myeloid hyperplasia and hypolobated megakaryocytes; (c, d) cytogenetic analysis showed a 46,XY,t(8;22)(p11;q11)[19]/46,XY[1]. Fluorescence in situ hybridization showed the split of one of the two fusion signals indicating a chromosome breakage in the FGFR1 locus; (e) low magnification of the bone marrow biopsy showing hypercellular marrow (hematoxylin and eosin); (f) reticulin stain demonstrating a mild grade of fibrosis.
Source publication
Hematopoietic myeloproliferative neoplasms with FGFR1 rearrangement result in the 8p11 myeloproliferative syndrome that in the current Word Health Organization classification is designated as “myeloid and lymphoid neoplasm with FGFR1 abnormalities.” We report the case of a 66-year-old man who had clinical features that resembled chronic myeloid leu...
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Citations
... These patients are resistant to current therapeutic regimens including tyrosine kinase inhibitors (TKIs) and have a 5-year survival rate of < 20% [2,3]. Currently, allogeneic hematopoietic stem-cell transplantation is the only potentially curative therapeutic option to prolong survival [3,4]. Thus, there is an urgent need for alternative treatment plans for patients who are either awaiting or unable to receive transplantation. ...
... These patients are resistant to current therapeutic regimens including tyrosine kinase inhibitors (TKIs) and have a 5-year survival rate of < 20% [2,3]. Currently, allogeneic hematopoietic stem-cell transplantation is the only potentially curative therapeutic option to prolong survival [3,4]. Thus, there is an urgent need for alternative treatment plans for patients who are either awaiting or unable to receive transplantation. ...
Background
Rearrangements involving the fibroblast growth factor receptor 1 (FGFR1) gene result in 8p11 myeloproliferative syndrome (EMS), which is a rare and aggressive hematological malignancy that is often initially diagnosed as myelodysplastic syndrome (MDS). Clinical outcomes are typically poor due to relative resistance to tyrosine kinase inhibitors (TKIs) and rapid transformation to acute leukemia. Deciphering the transcriptomic signature of FGFR1 fusions may open new treatment strategies for FGFR1 rearrangement patients.
Methods
DNA sequencing (DNA-seq) was performed for 20 MDS patients and whole exome sequencing (WES) was performed for one HOOK3-FGFR1 fusion positive patient. RNA sequencing (RNA-seq) was performed for 20 MDS patients and 8 healthy donors. Fusion genes were detected using the STAR-Fusion tool. Fluorescence in situ hybridization (FISH), quantitative real-time PCR (qRT-PCR), and Sanger sequencing were used to confirm the HOOK3-FGFR1 fusion gene. The phosphorylation antibody array was performed to validate the activation of nuclear factor-kappaB (NF-kappaB) signaling.
Results
We identified frequently recurrent mutations of ASXL1 and U2AF1 in the MDS cohort, which is consistent with previous reports. We also identified a novel in-frame HOOK3-FGFR1 fusion gene in one MDS case with abnormal monoclonal B-cell lymphocytosis and ring chromosome 8. FISH analysis detected the FGFR1 break-apart signal in myeloid blasts only. qRT-PCR and Sanger sequencing confirmed the HOOK3-FGFR1 fusion transcript with breakpoints located at the 11th exon of HOOK3 and 10th exon of FGFR1, and Western blot detected the chimeric HOOK3-FGFR1 fusion protein that is presumed to retain the entire tyrosine kinase domain of FGFR1. The transcriptional feature of HOOK3-FGFR1 fusion was characterized by the significant enrichment of the NF-kappaB pathway by comparing the expression profiling of FGFR1 fusion positive MDS with 8 healthy donors and FGFR1 fusion negative MDS patients. Further validation by phosphorylation antibody array also showed NF-kappaB activation, as evidenced by increased phosphorylation of p65 (Ser 536) and of IKBalpha (Ser 32).
Conclusions
The HOOK3-FGFR1 fusion gene may contribute to the pathogenesis of MDS and activate the NF-kappaB pathway. These findings highlight a potential novel approach for combination therapy for FGFR1 rearrangement patients.
... Translocation between chromosomes 8 and 22 leads to the formation of a protein similar to the BCR/ABL chimeric protein [3,4]. Accordingly, the clinical features of the patients with BCR-FGFR1 fusion gene are similar to chronic myeloid leukemia (CML) and thus may be misdiagnosed as CML [5][6][7]. These patients are resistant to tyrosine kinase inhibitor (TKI) therapy, so they are generally treated with chemotherapy and allogeneic stem cell transplantation (SCT). ...
... As for that, in 2016 WHO classification, myeloid/lymphoid neoplasm was identified according to rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2 [14]. Among these, myeloid/lymphoid neoplasm with rearrangement of FGFR1 gene is quite rare [5][6][7]15]. Due to clinical and laboratory features similar to CML, these patients are usually misdiagnosed. So, cytogenetic analysis and accurate molecular diagnosis is crucial [16]. ...
... FGFR1 gene has many fusion partner genes; the most frequent is the BCR gene. This new fusion protein activates tyrosine kinases and induces development of several hematologic malignancies [5]. Patients with FGFR1-BCR fusion transform frequently to AML and infrequently to ALL and lymphoid neoplasms after a short period of chronic phase [2]. ...
Myeloid/lymphoid neoplasm is a rare malignancy with an aggressive course and rapid transformation to acute myeloid leukemia (AML), or less frequently to acute lymphoblastic leukemia (ALL). Cases with t(8;22)(p11;q11) BCR-FGFR1 fusion gene may be misdiagnosed with chronic myeloid leukemia (CML), due to a very similar morphologic and clinical profile. We report a case of 48-year-old woman who complained of weakness and gastric pain. She had splenomegaly, eosinophilia, and elevated white blood cells. Bone marrow (BM) aspiration biopsy was performed with an initial diagnosis of CML. Cytogenetic analysis of the BM showed a 46,XX,t(8;22)(p11.2;q11.2). She was diagnosed with myeloid/lymphoid neoplasm with eosinophilia and rearrangement of FGFR1 gene. Throughout the chronic phase, the patient was treated with hydroxurea. Additional chromosomal abnormalities developed during therapy. Owing to the (8;22) clone, our patient did not respond to the treatment and rapidly transformed first to B-ALL and then AML. To the best of our knowledge, this is the first MPN patient with rearrangement of BCR and FGFR1 genes with rapid transformation to B-ALL and then to AML.
We report a case of a 20-year-old man who presented with splenomegaly, hyperleukocytosis, anemia, and thrombocytopenia. A diagnosis of acute myeloid leukemia (AML) with LRRFIP1::FGFR1 rearrangement with complex karyotype was determined. Chromosome analysis showed a male karyotype: 46,XY,i(1)(q10),t(2;8)(q37;p11.2),der(5)t(1;5) (p22;q13)[17]46,XY[3]. Fluorescence in situ hybridization (FISH) analysis using the Cytocell FGFR1 break apart/amplification probe detected FGFR1 rearrangement with t(2:8) in 126/200 cells analyzed. Other FISH probes including 1p36/ 1q25 probes, del(5q) deletion probe, TLX3 break apart probe, and PDGFRB break apart probe were also utilized to confirm the other karyotypic abnormalities. Next-generation sequencing (NGS) SureSelectXT Custom DNA Target Somatic Detection detected RUNX1 gene mutation. NGS Archer FusionPlex (RNA) confirmed the LRRFIP1::FGFR1 rearrangement. This is the second reported case of AML with LRRFIP1::FGFR1 rearrangement and the first with a complex karyotype.
In a registry-based analysis of 135 patients with “myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions” (MLN-TK; FIP1L1::PDGFRA, n = 78; PDGFRB, diverse fusions, n = 26; FGFR1, diverse, n = 9; JAK2, diverse, n = 11; ETV6::ABL1, n = 11), we sought to evaluate the disease-defining characteristics. In 81/135 (60%) evaluable patients, hypereosinophilia (>1.5 × 10⁹/l) was observed in 40/44 (91%) FIP1L1::PDGFRA and 7/7 (100%) ETV6::ABL1 positive patients but only in 13/30 (43%) patients with PDGFRB, FGFR1, and JAK2 fusion genes while 9/30 (30%) patients had no eosinophilia. Monocytosis >1 × 10⁹/l was identified in 27/81 (33%) patients, most frequently in association with hypereosinophilia (23/27, 85%). Overall, a blast phase (BP) was diagnosed in 38/135 (28%) patients (myeloid, 61%; lymphoid, 39%), which was at extramedullary sites in 18 (47%) patients. The comparison between patients with PDGFRA/PDGFRB vs. FGFR1, JAK2, and ETV6::ABL1 fusion genes revealed a similar occurrence of primary BP (17/104, 16% vs. 8/31 26%, p = 0.32), a lower frequency (5/87, 6% vs. 8/23, 35%, p = 0.003) of and a later progression (median 87 vs. 19 months, p = 0.053) into secondary BP, and a better overall survival from diagnosis of BP (17.1 vs. 1.7 years, p < 0.0008). We conclude that hypereosinophilia with or without monocytosis and various phenotypes of BP occur at variable frequencies in MLN-TK.
Background
Rearrangements involving the fibroblast growth factor receptor 1 (FGFR1) gene result in 8p11 myeloproliferative syndrome (EMS), which is a rare and aggressive hematological malignancy that is often initially diagnosed as myelodysplastic syndrome (MDS). Clinical outcomes are typically poor due to relative resistance to tyrosine kinase inhibitors (TKIs) and rapid transformation to acute leukemia. Deciphering the transcriptomic signature of FGFR1 fusions may open new treatment strategies for FGFR1 rearrangement patients.
Methods
DNA sequencing (DNA-seq) was performed for 20 MDS patients and whole exome sequencing (WES) was performed for one HOOK3-FGFR1 fusion positive patient. RNA sequencing (RNA-seq) was performed for 20 MDS patients and 8 healthy donors. Fusion genes were detected using the STAR-Fusion tool. Fluorescence in situ hybridization (FISH), quantitative real-time PCR (qRT-PCR), and Sanger sequencing were used to confirm the HOOK3-FGFR1 fusion gene. The phosphorylation antibody array was performed to validate the activation of nuclear factor-kappaB (NF-kappaB) signaling.
Results
We identified frequently recurrent mutations of ASXL1 and U2AF1 in the MDS cohort, which is consistent with previous reports. We also identified a novel in-frame HOOK3-FGFR1 fusion gene in one MDS case with abnormal monoclonal B-cell lymphocytosis and ring chromosome 8. FISH analysis detected the FGFR1 break-apart signal in myeloid blasts only. qRT-PCR and Sanger sequencing confirmed the HOOK3-FGFR1 fusion transcript with breakpoints located at the 11th exon of HOOK3 and 10th exon of FGFR1, and Western blot detected the chimeric HOOK3-FGFR1 fusion protein that is presumed to retain the entire tyrosine kinase domain of FGFR1. The transcriptional feature of HOOK3-FGFR1 fusion was characterized by the significant enrichment of the NF-kappaB pathway by comparing the expression profiling of FGFR1 fusion positive MDS with 8 healthy donors and FGFR1 fusion negative MDS patients. Further validation by phosphorylation antibody array also showed NF-kappaB activation, as evidenced by increased phosphorylation of p65 (Ser 536) and of IKBalpha (Ser 32).
Conclusion
The HOOK3-FGFR1 fusion gene may contribute to the pathogenesis of MDS and activate the NF-kappaB pathway. These findings highlight a potential novel approach for combination therapy for FGFR1 rearrangement patients.
Fibroblast Growth Factor Receptor Like 1 (FGFRL1) signalling has crucial role in a multitude of processes during genetic diseases, embryonic development and various types of cancer. Due to its partial structural similarity with its classical Fibroblast Growth Factor Receptor [FGFR] counterparts and lack of tyrosine kinase domain, FGFRL1 was thought to work as a decoy receptor in FGF/FGFR signalling. Later on, growing number evidences showed that expression of FGFRL1 affects major pathways like ERK1/2, Akt and others, which are dysfunctional in a wide range of human cancers. In this review, we provide an overview of the current understanding of FGFRL1 and its roles in cell differentiation, adhesion and proliferation pathways . Overexpression of FGFRL1 might lead to tumor progression and invasion. In this context, inhibitors for FGFRL1 might have therapeutic benefits in human cancer prognosis.
8p11 myeloproliferative syndrome (EMS) represents a unique WHO-classified hematologic malignancy defined by translocations of the FGFR1 receptor. The syndrome is a myeloproliferative neoplasm characterized by eosinophilia and lymphadenopathy, with risk of progression to either AML (acute myeloid leukemia) or T or B-lymphoblastic lymphoma/leukemia. Within the EMS subtype, translocations between Breakpoint Cluster Region (BCR) and Fibroblast Growth Factor Receptor 1 (FGFR1) have been shown to produce a dominant fusion protein that is notoriously resistant to tyrosine kinase inhibitors (TKIs). Here, we report two cases of BCR-FGFR1+ EMS identified via RNA-seq and confirmed by FISH. Sanger sequencing revealed that both cases harbored the exact same breakpoint. In the first case, the patient presented with AML-like disease, and in the second, the patient progressed to B-ALL. Additionally, we observed that that primary leukemia cells from Case 1 demonstrated sensitivity to the tyrosine kinase inhibitors Ponatinib and Dovitinib that can target FGFR1 kinase activity, while primary cells from Case 2 were resistant to both drugs. Taken together these results suggest that some but not all BCR-FGFR1 fusion positive leukemias may respond to TKIs that target FGFR1 kinase activity.
