|Gene:||ZMYM2; zinc finger MYM-type containing 2|
|Aliases: || FIM, MYM, RAMP, SCLL, ZNF198 |
|Summary:||The protein encoded by this gene is a zinc finger protein that may act as a transcription factor. The encoded protein may be part of a BHC histone deacetylase complex. Translocation of this gene with the fibroblast growth factor receptor-1 gene (FGFR1) results in a fusion gene, which may be a cause of stem cell leukemia lymphoma syndrome (SCLL). Several transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2010]|
|Databases:||OMIM, HGNC, Ensembl, GeneCard, Gene|
|Protein:||zinc finger MYM-type protein 2|
|Source:||NCBIAccessed: 31 August, 2019|
Research IndicatorsGraph generated 31 August 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: ZMYM2 (cancer-related)
An Y, Cai H, Zhang Y, et al.circZMYM2 Competed Endogenously with miR-335-5p to Regulate JMJD2C in Pancreatic Cancer.
Cell Physiol Biochem. 2018; 51(5):2224-2236 [PubMed
] Related Publications
BACKGROUND/AIMS: We aimed to study the involvement of circZMYM2 (hsa_circ_0099999) in pancreatic cancer (PC) cell proliferation, apoptosis and invasion and to figured out the underlying mechanism of circZMYM2 regulating miR-335-5p and JMJD2C.
METHODS: CircRNA differential expressions in twenty PC samples and paired normal tissue samples were analyzed using Arraystar Human CircRNA microarray V1. CircZMYM2 expression level was determined via qRT-PCR. The effects of circZMYM2 inhibition and overexpression on cell proliferation, cell apoptosis and cell invasion were investigated by CCK-8 assays, Flow cytometry assays and Transwell assays. An animal experiment on nude mice was put forward to test the influence of circZMYM2 knockdown on tumor growth. The relationship between circZMYM2, miR-335 and JMJD2C was verified by RNA pull down, dual-luciferase reporter assays and rescue experiment. The effect of circZMYM2 and miR-335-5p on the expression of JMJD2C protein was detected by western blot.
RESULTS: CircZMYM2 overexpression was observed in both PC tissues and cells. Knockdown of circZMYM2 inhibited proliferation, induced apoptosis, and weakened invasion ability of cancer cells. Tumor growth was restrained in vivo. CircZMYM2 repressed the expression of its target miR-335-5p. MiR-335-5p attenuated pancreatic cancer development via inhibition of JMJD2C.
CONCLUSION: Our study demonstrated that circZMYM2 promoted PC progression. CircZMYM2 had a sponge effect on miR-335-5p and modulated the downstream oncogene JMJD2C.
Strati P, Tang G, Duose DY, et al.Myeloid/lymphoid neoplasms with FGFR1 rearrangement.
Leuk Lymphoma. 2018; 59(7):1672-1676 [PubMed
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Myeloid/lymphoid neoplasms with FGFR1 rearrangement are a rare entity. We present a multicenter experience of 17 patients with FISH-confirmed FGFR1 rearrangement. The clinical presentation at diagnosis included myeloproliferative neoplasm (MPN) in 4 (24%) patients, acute leukemia (AL) in 7 (41%), and concomitant MPN with AL in 6 (35%). The two most frequently observed cytogenetic abnormalities were t(8;13)(p11.2;q12)(partner gene ZMYM2) and t(8;22)(p11.2; q11.2)(BCR). Seventy-eight percent of tested patients had a RUNX1 mutation, of whom all had AL. Overall response rate to frontline therapy was 69%, and 76% of patients subsequently received allogeneic stem cell transplant (ASCT). After a median follow-up of 11 months, median progression-free survival was 15 months and median overall survival was not reached. In conclusion, FGFR1-rearranged hematologic malignancies present with features of MPN and/or AL. FGFR1 and RUNX1 are therapeutic targets for ongoing and future clinical trials.
Chang K, Liu JH, Yu SC, Lin CWFGFR1 translocation with concurrent myeloproliferative neoplasm, systemic mastocytosis, and lymphoblastic lymphoma: a case report.
Hum Pathol. 2018; 74:114-121 [PubMed
] Related Publications
FGFR1 translocation may cause myeloid or lymphoid neoplasm but rarely systemic mastocytosis (SM). Conversely, SM is associated with myeloproliferative neoplasm (MPN) but rarely lymphoblastic lymphoma (LBL) or FGFR1 translocation. We report the first case of FGFR1 translocation in a patient with concurrent LBL, MPN, and SM. A 21-year-old male patient presented with diffuse lymphadenopathies and leukocytosis. TdT
Montenegro-Garreaud X, Miranda RN, Reynolds A, et al.Myeloproliferative neoplasms with t(8;22)(p11.2;q11.2)/BCR-FGFR1: a meta-analysis of 20 cases shows cytogenetic progression with B-lymphoid blast phase.
Hum Pathol. 2017; 65:147-156 [PubMed
] Related Publications
Rearrangements of FGFR1 result in the 8p11 myeloproliferative syndrome, a group of rare diseases that features a myeloproliferative neoplasm (MPN) that commonly progresses to lymphoblastic leukemia/lymphoma or acute myeloid leukemia. The most common partner of FGFR1 is ZMYM2, and patients with the ZMYM2-FGFR1 fusion often present with MPN and T-lymphoblastic lymphoma. There are 14 other partners that can fuse with FGFR1, and of interest is the BCR-FGFR1 fusion that results from t(8;22)(p11.2;q11.2). Patients with t(8;22) often show leukocytosis and present with an MPN resembling chronic myeloid leukemia or very rarely, with B-lymphoblastic leukemia (B-ALL). In this study, we analyzed the clinicopathological, cytogenetic, and molecular features of 2 new patients with the t(8;22)(p11.2;q11.2)/BCR-FGFR1 who presented with B-ALL. An underlying MPN became apparent when a morphologic remission of B-ALL was achieved after chemotherapy. We subsequently reviewed the literature and identified 18 additional cases reported with B-ALL in a background MPN or with the MPN as a chronic phase. Our data suggest that the t(8;22)(p11.2;q11.2)/BCR-FGFR1 may arise from a myeloid/B progenitor cell. It is important to recognize that neoplasms carrying the t(8;22)/BCR-FGFR1, although rare, can commonly with B lymphoblastic leukemia at the initial diagnosis, which could distract one from recognizing a possible underlying 8p11 myeloproliferative syndrome.
Fibroblast growth factor (FGF)2, FGF4, FGF7 and FGF20 are representative paracrine FGFs binding to heparan-sulfate proteoglycan and fibroblast growth factor receptors (FGFRs), whereas FGF19, FGF21 and FGF23 are endocrine FGFs binding to Klotho and FGFRs. FGFR1 is relatively frequently amplified and overexpressed in breast and lung cancer, and FGFR2 in gastric cancer. BCR-FGFR1, CNTRL-FGFR1, CUX1-FGFR1, FGFR1OP-FGFR1, MYO18A-FGFR1 and ZMYM2-FGFR1 fusions in myeloproliferative neoplasms are non-receptor-type FGFR kinases, whereas FGFR1-TACC1, FGFR2-AFF3, FGFR2-BICC1, FGFR2-PPHLN1, FGFR3-BAIAP2L1 and FGFR3-TACC3 fusions in solid tumors are transmembrane-type FGFRs with C-terminal alterations. AZD4547, BGJ398 (infigratinib), Debio-1347 and dovitinib are FGFR1/2/3 inhibitors; BLU9931 is a selective FGFR4 inhibitor; FIIN-2, JNJ-42756493, LY2874455 and ponatinib are pan-FGFR inhibitors. AZD4547, dovitinib and ponatinib are multi-kinase inhibitors targeting FGFRs, colony stimulating factor 1 receptor (CSF1R), vascular endothelial growth factor (VEGF)R2, and others. The tumor microenvironment consists of cancer cells and stromal/immune cells, such as cancer-associated fibroblasts (CAFs), endothelial cells, M2-type tumor-associating macrophages (M2-TAMs), myeloid-derived suppressor cells (MDSCs) and regulatory T cells. FGFR inhibitors elicit antitumor effects directly on cancer cells, as well as indirectly through the blockade of paracrine signaling. The dual inhibition of FGF and CSF1 or VEGF signaling is expected to enhance the antitumor effects through the targeting of immune evasion and angiogenesis in the tumor microenvironment. Combination therapy using tyrosine kinase inhibitors (FGFR or CSF1R inhibitors) and immune checkpoint blockers (anti-PD-1 or anti-CTLA-4 monoclonal antibodies) may be a promising choice for cancer patients. The inhibition of FGF19-FGFR4 signaling is associated with a risk of liver toxicity, whereas the activation of FGF23-FGFR4 signaling is associated with a risk of heart toxicity. Endocrine FGF signaling affects the pathophysiology of cancer patients who are prescribed FGFR inhibitors. Whole-genome sequencing is necessary for the detection of promoter/enhancer alterations of FGFR genes and rare alterations of other genes causing FGFR overexpression. To sustain the health care system in an aging society, a benefit-cost analysis should be performed with a focus on disease-free survival and the total medical cost before implementing genome-based precision medicine for cancer patients.
Acute myelogenous leukemia (AML) has an overall poor survival rate and shows considerable molecular heterogeneity in its etiology. In the WHO classification there are >50 cytogenetic subgroups of AML, many showing highly specific chromosome translocations that lead to constitutive activation of individual kinases. In a rare stem cell leukemia/lymphoma syndrome, translocations involving 8p11 lead to constitutive activation of the fibroblast growth factor receptor 1 (FGFR1) kinase. This disorder shows myeloproliferative disease with almost invariable progresses to AML and conventional therapeutic strategies are largely unsuccessful. Because of the rare nature of this syndrome, models that faithfully recapitulate the human disease are needed to evaluate therapeutic strategies. The t(8;13)(p11;q12) chromosome translocation is most common rearrangement seen in this syndrome and creates a ZMYM2-FGFR1 chimeric kinase. To understand more about the molecular etiology of AML induced by this particular rearrangement, we have created a model human CD34+ cells transplanted into immunocompromized mice which develop myeloproliferative disease that progresses to AML with a long (>12 months) latency period. As in humans, these mice show hepatospenomegaly, hypercellular bone marrow and a CD45 + CD34 + CD13+ immunophenotype. Molecular studies demonstrate upregulation of genes such as KLF4 and FLT3 that promote stemness, and overexpression of MYC, which is associated with suppression of myeloid cell differentiation. This murine model, therefore, provides an opportunity to develop therapeutic strategies against the most common subtype within these FGFR1 driven neoplasms and study the molecular etiology in more depth.
Labonne JD, Vogt J, Reali L, et al.A microdeletion encompassing PHF21A in an individual with global developmental delay and craniofacial anomalies.
Am J Med Genet A. 2015; 167A(12):3011-8 [PubMed
] Related Publications
In Potocki-Shaffer syndrome (PSS), the full phenotypic spectrum is manifested when deletions are at least 2.1 Mb in size at 11p11.2. The PSS-associated genes EXT2 and ALX4, together with PHF21A, all map to this region flanked by markers D11S1393 and D11S1319. Being proximal to EXT2 and ALX4, a 1.1 Mb region containing 12 annotated genes had been identified by deletion mapping to explain PSS phenotypes except multiple exostoses and parietal foramina. Here, we report a male patient with partial PSS phenotypes including global developmental delay, craniofacial anomalies, minor limb anomalies, and micropenis. Using microarray, qPCR, RT-qPCR, and Western blot analyses, we refined the candidate gene region, which harbors five genes, by excluding two genes, SLC35C1 and CRY2, which resulted in a corroborating role of PHF21A in developmental delay and craniofacial anomalies. This microdeletion contains the least number of genes at 11p11.2 reported to date. Additionally, we also discuss the phenotypes observed in our patient with respect to those of published cases of microdeletions across the Potocki-Shaffer interval.
Chronic hepatitis B virus (HBV) infection is a major risk factor for developing hepatocellular carcinoma (HCC), and HBV X protein (HBx) acts as cofactor in hepatocarcinogenesis. In liver tumors from animals modeling HBx- and HBV-mediated hepatocarcinogenesis, downregulation of chromatin regulating proteins SUZ12 and ZNF198 induces expression of several genes, including epithelial cell adhesion molecule (EpCAM). EpCAM upregulation occurs in HBV-mediated HCCs and hepatic cancer stem cells, by a mechanism not understood. Herein we demonstrate HBx induces EpCAM expression via active DNA demethylation. In hepatocytes, EpCAM is silenced by polycomb repressive complex 2 (PRC2) and ZNF198/LSD1/Co-REST/HDAC1 chromatin-modifying complexes. Cells with stable knockdown of SUZ12, an essential PRC2 subunit, upon HBx expression demethylate a CpG dinucleotide located adjacent to NF-κB/RelA half-site. This NF-κB/RelA site is in a CpG island downstream from EpCAM transcriptional start site (TSS). Chromatin immunoprecipitation (ChIP) assays demonstrate HBx-dependent RelA occupancy of NF-κB half-site, whereas RelA knockdown suppresses CpG demethylation and EpCAM expression. Tumor necrosis factor-α activates RelA, propagating demethylation to nearby CpG sites, shown by sodium bisulfite sequencing. RelA-dependent demethylation occurring upon HBx expression requires methyltrasferase EZH2, TET2 a key factor in cytosine demethylation and inactive DNMT3L, shown by knockdown assays and sodium bisulfite sequencing. Co-immunoprecipitations and sequential ChIP assays demonstrate that RelA in the presence of HBx forms a complex with EZH2, TET2 and DNMT3L, although the role of DNMT3L remains to be understood. Interestingly, the human EpCAM gene also has a CpG island downstream from its TSS, and a NF-κB-binding site flanked by CpGs. HepG2 cells derived from human HCC exhibit demethylation of these NF-κB-flanking CpG sites, and HBV replication propagates demethylation to nearby CpG sites. DLK1, another PRC2 target gene, also upregulated in HBV-mediated HCCs, is demethylated in liver tumors at CpG dinucleotides flanking the NF-κB-binding sequence, supporting that this active DNA demethylation mechanism functions during oncogenic transformation.
Kumar KR, Chen W, Koduru PR, Luu HSMyeloid and lymphoid neoplasm with abnormalities of FGFR1 presenting with trilineage blasts and RUNX1 rearrangement: a case report and review of literature.
Am J Clin Pathol. 2015; 143(5):738-48 [PubMed
] Related Publications
OBJECTIVES: Myeloid and lymphoid neoplasms with abnormalities of fibroblast growth factor receptor 1 gene (FGFR1) are a rare and aggressive disease group that harbors translocations of FGFR1 with at least 14 recognized partner genes. We report a case of a patient with a novel t(17;21)(p13;q22) with RUNX1 rearrangement and trilineage blasts.
METHODS: A 29-year-old man with relapsed T-lymphoblastic lymphoma in the cervical nodes showed a myeloproliferative neoplasm in his bone marrow with three separate populations of immunophenotypically aberrant myeloid, T-lymphoid, and B-lymphoid blasts by flow cytometry. Cytogenetic and fluorescent in situ hybridization studies showed unique dual translocations of t(8;13)(p11.2;q12) and t(17;21)(p13;q22) with RUNX1 rearrangement.
RESULTS: The patient was initiated on a mitoxantrone, etoposide, and cytarabine chemotherapy regimen and died of complications of disease 1 month later.
CONCLUSIONS: To our knowledge, this is the first reported case of a myeloid and lymphoid neoplasm with abnormalities of FGFR1 with t(17;21)(p13;q22) and trilineage blasts.
Elucidating mechanisms of hepatitis B virus (HBV)-mediated hepatocarcinogenesis is needed to gain insights into the etiology and treatment of liver cancer. Cells where HBV is replicating exhibit increased expression of Plk1 kinase and reduced levels of two transcription repression factors, SUZ12 and ZNF198. SUZ12 is an essential subunit of the transcription repressive complex PRC2. ZNF198 stabilizes the transcription repressive complex composed of LSD1, Co-REST, and HDAC1. These two transcription repressive complexes are held together by binding the long noncoding RNA HOTAIR. In this study, we linked these regulatory events mechanistically by showing that Plk1 induces proteasomal degradation of SUZ12 and ZNF198 by site-specific phosphorylation. Plk1-dependent ubiquitination of SUZ12 and ZNF198 was enhanced by expression of HOTAIR, significantly reducing SUZ12 and ZNF198 stability. In cells expressing the HBV X protein (HBx), downregulation of SUZ12 and ZNF198 mediated global changes in histone modifications. In turn, HBx-expressing cells propagated an altered chromatin landscape after cell division, as exemplified by changes in histone modifications of the EpCAM promoter, a target of PRC2 and LSD1/Co-REST/HDAC1 complexes. Notably, liver tumors from X/c-myc bitransgenic mice exhibited downregulation of SUZ12 and ZNF198 along with elevated expression of Plk1, HOTAIR, and EpCAM. Clinically, similar effects were documented in a set of HBV-related liver tumors consistent with the likelihood that downregulation of SUZ12 and ZNF198 leads to epigenetic reprogramming of infected hepatocytes. Because both Plk1 and HOTAIR are elevated in many human cancers, we propose that their combined effects are involved in epigenetic reprogramming associated broadly with oncogenic transformation.
Nam SW, Park KC, Choi HS, et al.Identification of Zinc Finger, MYM-type 2 (ZMYM2) as a regulator of sorafenib resistance in hepatocellular carcinoma cell lines.
J Gastroenterol Hepatol. 2014; 29(3):633-9 [PubMed
] Related Publications
BACKGROUND AND AIM: Hepatocellular carcinoma (HCC) is an aggressive malignancy with a very complex molecular process. There is no successful therapy for advanced HCC at present. Recently, sorafenib has been used as a systemic therapy to improve survival in patients with advanced HCC, but increasing reports of recurrence or non-responsiveness indicate the limitations of sorafenib as a therapeutic agent. Therefore, identification of genes involved in sorafenib resistance is important to effectively treat advanced HCC.
METHODS: We performed a genomic screening with a short-hairpin RNA library cassette on HCC cell lines to find genes relating resistance to sorafenib.
RESULTS: Zinc finger, MYM type 2 (ZMYM2) was sequenced after three successive screens in vitro as a challengeable target. The inhibition of ZMYM2 resulted in sorafenib-resistance in formerly sensitive HCC cell lines. Immunohistochemical comparison of tumor and non-tumor regions showed stronger ZMYM2 staining intensities in non-tumor regions than in tumor regions.
CONCLUSION: ZMYM2 may play an important role in sorafenib resistance.
Trimaldi J, Carballido EM, Bowers JW, et al.B-lymphoblastic leukemia/lymphoma associated with t(8;13)(p11;q12)/ ZMYM2 (ZNF198)-FGFR1 : rare case and review of the literature.
Acta Haematol. 2013; 130(3):127-34 [PubMed
] Related Publications
Myeloid and lymphoid neoplasms with fibroblastic growth factor receptor-1 (FGFR1) abnormalities originate from mutated pluripotent stem cells and have a heterogeneous clinical presentation. There are 12 identified partner genes commonly involved in FGFR1 translocation at an 8p11 breakpoint. In FGFR1-related neoplasms, T-lymphoblastic lymphoma with eosinophilia is the most common clinical scenario, whereas acute B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) is rare. To date, only 7 cases of B-ALL/LBL with FGFR1 abnormalities have been reported. Here, we report an additional case of a 64-year-old gentleman with leukocytosis, eosinophilia and diffuse mediastinal and general lymphadenopathy. Bone marrow examination showed patchy infiltrates of immature precursors/blasts, along with myeloid/eosinophilic hyperplasia. Immunophenotyping confirmed increased B lymphoblasts (30-40%). Karyotyping revealed cytogenetic abnormalities, including t(8;13)(p11;q12)/ZMYM2 (ZNF198)-FGFR1 and trisomy 21. The patient did not respond to hyper-CVAD chemotherapy and within 4 months developed acute myelomonocytic leukemia and expired 11 months after the initial diagnosis. Similar cases from the literature are reviewed.
This review focuses on the significance of deregulation of epigenetic mechanisms by the hepatitis B virus (HBV) X protein in hepatocarcinogenesis and HBV replication. Epigenetic mechanisms, DNA methylation, and specific histone modifications, e.g., trimethylation of H3 on lysine-27 or lysine-4, maintain 'cellular memory' by silencing expression of lineage-inducing factors in stem cells and conversely, of pluripotency factors in differentiated cells. The X protein has been reported to induce expression of DNA methyltransferases (DNMTs), likely promoting epigenetic changes during hepatocarcinogenesis. Furthermore, in cellular and animal models of X-mediated oncogenic transformation, protein levels of chromatin modifying proteins Suz12 and Znf198 are down-regulated. Suz12 is essential for the Polycomb Repressive Complex 2 (PRC2) mediating the repressive trimethylation of H3 on lysine-27 (H3K27me3). Znf198, stabilizes the LSD1-CoREST-HDAC complex that removes, via lysine demethylase1 (LSD1), the activating trimethylation of H3 on lysine-4 (H3K4me3). Down-regulation of Suz12 also occurs in liver tumors of woodchucks chronically infected by woodchuck hepatitis virus, an animal model recapitulating HBV-mediated hepatocarcinogenesis in humans. Significantly, subgroups of HBV-induced liver cancer re-express hepatoblast and fetal markers, and imprinted genes, suggesting hepatocyte reprogramming during oncogenic transformation. Lastly, down-regulation of Suz12 and Znf198 enhances HBV replication. Collectively, these observations suggest deregulation of epigenetic mechanisms by HBV X protein influences both the viral cycle and the host cell.
UNLABELLED: Chronic hepatitis B virus (HBV) infection is a major risk factor for developing liver cancer, and the HBV X protein (pX) has been implicated as a cofactor in hepatocyte transformation. We have shown that HBV replication as well as in vitro transformation by pX are associated with induction of the mitotic polo-like kinase 1 (Plk1) and down-regulation of the chromatin remodeling components Suz12 and Znf198. Herein, we demonstrate the same inverse relationship between Plk1 and Suz12/Znf198 in liver tumors from X/c-myc bitransgenic mice and woodchuck hepatitis virus (WHV)-infected woodchucks. Employing these animal models and the HBV replicating HepAD38 cells we examined the effect of Suz12/Znf198 down-regulation on gene expression. Genes analyzed include hepatic cancer stem cell markers BAMBI, DKK1,2, DLK1, EpCAM, MYC, and proliferation genes CCNA1, CCND2, IGFII, MCM4-6, PLK1, RPA2, and TYMS. Suz12 occupancy at the promoters of BAMBI, CCND2, DKK2, DLK1, EpCAM, and IGFII was demonstrated by chromatin immunoprecipitation in untransformed hepatocytes, but was markedly reduced in pX-transformed and Suz12 knockdown cells. Accordingly, we refer to these genes as "Suz12 repressed" genes in untransformed hepatocytes. The Suz12 repressed genes and proliferation genes were induced in HBV-replicating HepAD38 cells and, interestingly, they exhibited distinct expression profiles during hepatocellular carcinoma (HCC) progression in X/c-myc bitransgenics. Specifically, CCND2, EpCAM, and IGFII expression was elevated at the proliferative and preneoplastic stages in X/c-myc bitransgenic livers, whereas BAMBI and PLK1 were overexpressed in hepatic tumors from X/c-myc bitransgenics and WHV-infected woodchucks. Importantly, most of these genes were selectively up-regulated in HBV-induced HCCs.
CONCLUSION: The distinct expression profile of the identified Suz12 repressed genes in combination with the proliferation genes hold promise as biomarkers for progression of chronic HBV infection to HCC.
Mayeur-Rousse C, Sorel N, Voldoire M, et al.Unique association of systemic mastocytosis and myeloid/lymphoid neoplasm in blast crisis with abnormality of FGFR1 gene.
Leuk Res. 2012; 36(3):377-81 [PubMed
] Related Publications
Chromosomal translocations and activation of the fibroblast growth factor (FGF) receptor 1 (FGFR1) are a feature of stem cell leukemia-lymphoma syndrome (SCLL), an aggressive malignancy characterized by rapid transformation to acute myeloid leukemia and lymphoblastic lymphoma. It has been suggested that FGFR1 proteins lose their ability to recruit Src kinase, an important mediator of FGFR1 signaling, as a result of the translocations that delete the extended FGFR substrate-2 (FRS2) interacting domain that Src binds. In this study, we report evidence that refutes this hypothesis and reinforces the notion that Src is a critical mediator of signaling from the FGFR1 chimeric fusion genes generated by translocation in SCLL. Src was constitutively active in BaF3 cells expressing exogenous FGFR1 chimeric kinases cultured in vitro as well as in T-cell or B-cell lymphomas they induced in vivo. Residual components of the FRS2-binding site retained in chimeric kinases that were generated by translocation were sufficient to interact with FRS2 and activate Src. The Src kinase inhibitor dasatinib killed transformed BaF3 cells and other established murine leukemia cell lines expressing chimeric FGFR1 kinases, significantly extending the survival of mice with SCLL syndrome. Our results indicated that Src kinase is pathogenically activated in lymphomagenesis induced by FGFR1 fusion genes, implying that Src kinase inhibitors may offer a useful option to treatment of FGFR1-associated myeloproliferative/lymphoma disorders.
The ZMYM2-FGFR1 (formerly known as ZNF198-FGFR1) fusion kinase induces stem cell leukemia-lymphoma syndrome (SCLL), a hematologic malignancy characterized by rapid transformation to acute myeloid leukemia and T-lymphoblastic lymphoma. In the present study, we demonstrate frequent, constitutive activation of Notch1 and its downstream target genes in T-cell lymphomas that arose in a murine model of ZMYM2-FGFR1 SCLL. Notch up-regulation was also demonstrated in human SCLL- and FGFR1OP2-FGFR1-expressing KG-1 cells. To study the role of Notch in T-cell lymphomagenesis, we developed a highly tumorigenic cell line from ZMYM2-FGFR1-expressing cells. Pharmacologic inhibition of Notch signaling in these cells using γ-secretase inhibitors significantly delayed leukemogenesis in vivo. shRNA targeting of Notch1, as well as c-promoter-binding factor 1 (CBF1) and mastermind-like 1 (MAML1), 2 essential cofactors involved in transcriptional activation of Notch target genes, also significantly delayed or inhibited tumorigenesis in vivo. Mutation analysis demonstrated that 5' promoter deletions and alternative promoter usage were responsible for constitutive activation of Notch1 in all T-cell lymphomas. These data demonstrate the importance of Notch signaling in the etiology of SCLL, and suggest that targeting this pathway could provide a novel strategy for molecular therapies to treat SCLL patients.
UNLABELLED: Chronic hepatitis B virus (HBV) infection is a major etiologic factor in hepatocellular carcinoma (HCC) pathogenesis, involving effects of chronic liver inflammation and of the weakly oncogenic HBV X protein (pX). pX-mediated hepatocyte transformation requires Polo-like kinase1 (Plk1) activity, but the mechanism is not fully understood. We identified by a genome-wide short hairpin RNA (shRNA) library screen the genes zinc finger, MYM-type 2 (ZNF198) and suppressor of zeste 12 homolog (Drosophila) (SUZ12) whose protein depletion rescues pX-expressing cells from DNA damage-induced apoptosis. ZNF198 and SUZ12 are components of chromatin remodeling complexes and associate with promyelocytic leukemia (PML) nuclear bodies. Knockdown of ZNF198 and SUZ12 by small interfering RNA (siRNA) reduced p53 stability and DNA repair, rescued pX-expressing hepatocytes from DNA damage-induced apoptosis, and increased pX-induced polyploidy and oncogenic transformation, suggesting ZNF198 and SUZ12 have a role in pX-mediated transformation. Interestingly, during pX-mediated transformation the protein but not messenger RNA (mRNA) levels of ZNF198 and SUZ12 progressively decreased, whereas Plk1 levels increased. Inhibition of Plk1 activity restored protein levels of ZNF198 and SUZ12. In addition, transfected Polo-box-domain (PBD) of Plk1 coimmunoprecipitated with ZNF198 and SUZ12, suggesting that these proteins are Plk1 substrates. Elevated Plk1 and reduced protein levels of ZNF198 and SUZ12 were also observed in human liver cancer cell lines derived from HBV-related tumors and in the presence of HBV replication. Importantly, knockdown by siRNA of ZNF198 and SUZ12 enhanced HBV replication.
CONCLUSION: Reduced protein levels of ZNF198 and SUZ12 and elevated Plk1 occur during pX-mediated hepatocyte transformation in human liver cancer cell lines, as well as during HBV replication, underscoring the significance of these genes both in HBV-mediated HCC pathogenesis and HBV replication. We propose Plk1 activity down-regulates ZNF198 and SUZ12, thereby enhancing both HBV replication and pX-mediated oncogenic transformation.
de Brito LR, Batey MA, Zhao Y, et al.Comparative pre-clinical evaluation of receptor tyrosine kinase inhibitors for the treatment of multiple myeloma.
Leuk Res. 2011; 35(9):1233-40 [PubMed
] Related Publications
BACKGROUND: Fibroblast growth factor receptor 3 (FGFR3) is up-regulated as a result of the t(4;14)(p16;q32) translocation that occurs in up to 20% of multiple myeloma (MM) patients. Recent studies have demonstrated that up-regulation of FGFR3 promotes cell survival, growth and drug resistance in malignant plasma cells, both in vitro and in vivo. Therefore, inhibition of FGFR3 signalling is potential target for the chemotherapeutic intervention in t(4;14) MM.
METHODS: Small molecule receptor tyrosine kinase inhibitors (PD173074, sunitinib (SU-11248), vandetanib (ZD6474) and vatalanib (PTK-787)) with varying degrees of inhibitory activity and selectivity against FGFR, were assessed in Ba/f3 cells expressing ZNF198-FGFR1 and MM cell lines. Cell viability, FGFR3 and ZNF198-FGFR1 phosphorylation and apoptosis were evaluated by growth inhibition assays, immunoblotting and fluorescence-activated cell sorting analysis, respectively. An in vivo study was performed with sunitinib in t(4;14)-positive and t(4;14)-negative human MM tumour xenograft models.
RESULTS: PD173074 and sunitinib differentially inhibited the growth of Ba/f3 cells expressing ZNF198-FGFR1 (GI(50)=10 nM and 730 nM, versus GI(50) >1 μM and 2.7 μM for parental cells; p<0.0001) and t(4;14) positive MM cell lines (GI(50)=4-10 μM and 1-3 μM, versus GI(50)=14-15 μM and 4-5 μM for t(4;14) negative MM cells; p≤0.002). In addition, both PD173074 and sunitinib inhibited the activation of FGFR3 in t(4;14)-positive MM cells. PD173074 and sunitinib induced an apoptotic response in a concentration and time-dependent manner in a t(4;14)-positive (PD174073 and sunitinib) but not a t(4;14)-negative MM cell line (sunitinib only); however, in in vivo tumours derived from the same cell lines, sunitinib was only active in the t(4;14)-negative model.
CONCLUSIONS: These data demonstrate that PD173074 and sunitinib are inhibitors of FGFR3 in MM cell lines, and that sunitinib has in vivo activity in a human MM tumour xenograft model. However, caution should be exercised in using the t(4;14) translocation as a predictive biomarker for patient selection in clinical trials with sunitinib.
Yan Z, Yang B, Wang QS, et al.[Clinical pathological features of the 8p11 myeloproliferative syndrome].
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2010; 18(5):1321-6 [PubMed
] Related Publications
This study was aimed to investigate the clinico-pathological features, diagnosis and treatment of the 8p11 (eight p11) myeloproliferative syndrome (EMS). Morphological changes of cells were evaluated by bone marrow smear and biopsy. The cell immunophenotypes were analysed by flow cytometry. Karyotypes were determined by conventional cytogenetic method, and bcr/abl fusion gene was detected by reverse transcription-polymerase chain reaction (RT-PCR). The results indicated that EMS was a relatively rare disease characterized by the occurrence of a bcr/abl-negative myeloproliferative disorder and a T-cell lymphoblastic lymphoma (T-LBL). Bone marrow examination showed myeloid hyperplasia or myeloproliferative neoplasm, often accompanied by eosinophilia. Flow cytometric immunophenotyping showed increased myelomonoblasts; cytogenetic analysis showed a translocation at the 8p11 locus; RT-PCR demonstrated non bcr/abl fusion gene. At the molecular level, all cases carried a chromosomal abnormality involving the fibroblast growth factor receptor 1 (FGFR1) at chromosome 8p11. Up to now, 11 partner genes have been identified and associated with FGFR1 rearrangements. The most common partner is ZNF198 on chromosome 13q11-12. Majority of patients terminate in acute myeloid leukemia which is resistant to conventional chemotherapy. Currently, the only curative option appears to be allogeneic hematopoietic stem cell transplantation. In conclusion, EMS is myeloid and lymphoid neoplasm, associates with FGFR1 rearrangements. It is usually misdiagnosed as T-LBL, atypical chronic myeloid leukemia (aCML) or chronic myelogenous-monocytic leukemia (CMML). Timely cytogenetic and molecular biological examination is vital in order to avoid misdiagnosis and mistreatment.
Chen X, Zhang Y, Li Y, et al.Biphenotypic hematologic malignancy: a case report of the 8p11 myeloproliferative syndrome in a child.
J Pediatr Hematol Oncol. 2010; 32(6):501-3 [PubMed
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SUMMARY: The 8p11 myeloproliferative syndrome, also known as stem cell leukemia/lymphoma, is a rare, atypical, myeloproliferative disorder and lymphoid malignancy associated with chromosomal abnormalities involving the 8p11 chromosomal band. Translocations associated with this syndrome result in the fusion of the fibroblast growth factor receptor 1 (FGFR 1) gene with various partners, resulting in ligand-independent FGFR activity. To date, 8 partner genes have been identified in association with FGFR1 rearrangements. The most frequent FGFR1 translocation partner is the zinc finger gene ZNF198 located at 13q11. Disease phenotypes associated with this translocation include poor prognosis and transformation to acute leukemia and non-Hodgkin lymphoma. In common with a T-cell phenotype, obtaining and maintaining remission is difficult by conventional chemotherapy. This study describes an illustrative case of 8p11 myeloproliferative syndrome/stem cell leukemia/lymphoma outlining its chief features and historical developments.
Zhang WW, Habeebu S, Sheehan AM, et al.Molecular monitoring of 8p11 myeloproliferative syndrome in an infant.
J Pediatr Hematol Oncol. 2009; 31(11):879-83 [PubMed
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The 8p11 myeloproliferative syndrome is a rare hematologic malignancy derived from a pluripotent hematopoietic stem cell associated with rearrangements involving the fibroblast growth factor receptor 1 (FGFR1) gene located on chromosome 8p11. The most common translocation, t(8;13) (p11;q13), results in a ZNF198-FGFR1 fusion gene and constitutively active FGFR1 tyrosine kinase activity. Typical pathologic findings include myeloid hyperplasia, lymphadenopathy, precursor T-lymphoblastic lymphoma, and eosinophilia. The disease is usually associated with an aggressive course and progression to acute myeloid leukemia is frequent. We report here the first case of 8p11 myeloproliferative syndrome in an infant and demonstrate the value of molecular testing in the diagnosis and minimal disease monitoring of this rare disease.
BACKGROUND: Chimeric oncogenes encoding constitutively active protein tyrosine kinases are associated with chronic myeloid neoplasms. TEL-PDGFRbeta (TPbeta, also called ETV6-PDGFRB) is a hybrid protein produced by the t(5;12) translocation, FIP1L1-PDGFRalpha (FPalpha) results from a deletion on chromosome 4q12 and ZNF198-FGFR1 is created by the t(8;13) translocation. These fusion proteins are found in patients with myeloid neoplasms associated with eosinophilia. Wild-type receptor tyrosine kinases are efficiently targeted for degradation upon activation, in a process that requires Cbl-mediated monoubiquitination of receptor lysines. Since protein degradation pathways have been identified as useful targets for cancer therapy, the aim of this study was to compare the degradation of hybrid and wild-type receptor tyrosine kinases.
DESIGN AND METHODS: We used Ba/F3 as a model cell line, as well as leukocytes from two patients, to analyze hybrid protein degradation.
RESULTS: In contrast to the corresponding wild-type receptors, which are quickly degraded upon activation, we observed that TPbeta, FPalpha and the ZNF198-FGFR1 hybrids escaped down-regulation in Ba/F3 cells. The high stability of TPbeta and FPalpha hybrid proteins was confirmed in leukocytes from leukemia patients. Ubiquitination of TPbeta and FPalpha was much reduced compared to that of wild-type receptors, despite marked Cbl phosphorylation in cells expressing hybrid receptors. The fusion of a destabilizing domain to TPbeta induced protein degradation. Instability was reverted by adding the destabilizing domain ligand, Shield1. The destabilization of this modified TPbeta reduced cell transformation and STAT5 activation.
CONCLUSIONS: We have shown that chimeric receptor tyrosine kinases escape ubiquitination and down-regulation and that their stabilization is critical to efficient stimulation of cell proliferation.
Ren M, Li X, Cowell JKGenetic fingerprinting of the development and progression of T-cell lymphoma in a murine model of atypical myeloproliferative disorder initiated by the ZNF198-fibroblast growth factor receptor-1 chimeric tyrosine kinase.
Blood. 2009; 114(8):1576-84 [PubMed
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A mouse model of human ZNF198-fibroblast growth factor receptor-1 (FGFR1) stem cell leukemia lymphoma has been developed to investigate mechanisms of oncogenesis and progression. Using array-based comparative genomic hybridization, we followed disease progression after serial transplantation of ZNF198-FGFR1-transformed stem cells that give rise to a distinct myeloproliferative disorder and T-lymphoblastic leukemia. A consistent, frequently homozygous, chr14:53880459-55011545 deletion, containing the T-cell receptor alpha and delta genes, was identified in the bone marrow, spleen, and lymph nodes in all cases. The absence of cell-surface T-cell receptor alpha in tumor cells precludes CD3 recruitment, resulting in loss of a functional T-cell receptor complex, supporting the idea that prevention of maturation of CD4(+)/CD8(+) double-positive immature T cells is important in ZNF198-FGFR1 disease development. Up-regulation of the B-cell line 2, interleukin 7 receptor alpha and interleuking 2 receptor alpha prosurvival genes in these undifferentiated tumor precursor cells suggests one mechanism that allows them to escape apoptosis in the thymus. Thus, we have defined an important event in the process of ZNF198-FGFR1-induced T-cell leukemia.
Mozziconacci MJ, Carbuccia N, Prebet T, et al.Common features of myeloproliferative disorders with t(8;9)(p12;q33) and CEP110-FGFR1 fusion: report of a new case and review of the literature.
Leuk Res. 2008; 32(8):1304-8 [PubMed
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The 8p12 myeloproliferative syndrome is a rare, generally aggressive chronic myeloproliferative disorder (MPD). The hallmark of this MPD is the disruption of the FGFR1 gene, which encodes a tyrosine kinase receptor for members of the fibroblast growth factor family. In MPD cells FGFR1 is fused to several partners. The most frequent partner genes are BCR, CEP110, FOP, and ZNF198, localized on 22q11, 9q33, 6q27, and 13q12, respectively. We report here the tenth case of translocation (8;9)(p12;q33) in an acute myelomonocytic leukemia and provide a review of the literature that points to common syndrome features: the t(8;9)(p11;q33) MPD transforms rapidly, and always in myelomonocytic leukemia, with a possible B- or T-lymphoid involvement, which may include tonsil invasion. The FGFR1-MPD seems refractory to current chemotherapies and is not sensitive to imatinib. Currently, only the patients with bone marrow transplantation stand a chance of survival.
Sahin F, Sercan Z, Ertan Y, et al.Rapid transformation of atypical myeloproliferative disorder with consistent t(8;13) to B-cell acute lymphoblastic leukemia: a case report.
Hematology. 2007; 12(6):489-92 [PubMed
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8p11 myeloproliferative syndrome (EMS; also known as the stem cell leukemia syndrome-SCLL) is a rare atypical myeloproliferative disorder associated with chromosomal abnormalities involving the 8p11 chromosomal band. Translocations associated with this syndrome result in the fusion of the fibroblast growth factor receptor 1 (FGFR 1) gene with various partners, resulting in ligand independent FGFR activity. The most commonly observed translocation of this syndrome is t(8;13), which results in the expression of a chimeric ZNF198-FGFR1 tyrosine kinase. Disease phenotype associated with this translocation has some typical features such as poor prognosis, and transformation to mainly acute leukemia and non-Hodgkin lymphoma; commonly with a T-cell phenotype in which obtaining and maintenance of remission is difficult by conventional chemotherapy. We hereby present a case diagnosed as atypical chronic myeloproliferative disease with consistent t(8;13)(p12;q12) and transformed rapidly to pre-B-cell acute lymphoblastic leukemia which is a rare clinical presentation.
Human 8p11 stem cell leukemia/lymphoma syndrome usually presents as a myeloproliferative disorder (MPD) that evolves to acute myeloid leukemia and/or lymphoma. The syndrome associated with t(8;13)(p11;q12) results in expression of the ZNF198-FGFR1 fusion tyrosine kinase that plays a pathogenic role in hematopoietic transformation. We found that ZNF198-FGFR1 activated both the AKT and mitogen activated protein kinase (MAPK) prosurvival signaling pathways, resulting in elevated phosphorylation of the AKT target FOXO3a at T32 and BAD at S112, respectively. These phosphorylated residues subsequently sequestered the proapoptotic FOXO3a and BAD to 14-3-3 to prevent apoptosis. We used a peptide-based 14-3-3 competitive antagonist, R18, to disrupt 14-3-3-ligand association. Expression of R18 effectively induced apoptosis in hematopoietic Ba/F3 cells transformed by ZNF198-FGFR1 compared with control cells. Moreover, purified recombinant transactivator of transcription (TAT)-conjugated R18 proteins effectively transduced into human leukemia cells and induced significant apoptosis in KG-1a cells expressing FGFR1OP2-FGFR1 fusion tyrosine kinase but not in control HL-60 and Jurkat T cells. Surprisingly, R18 was only able to dissociate FOXO3a, but not BAD as previously proposed, from 14-3-3 binding and induced apoptosis partially through liberation and reactivation of FOXO3a. Our findings suggest that 14-3-3 integrates prosurvival signals in FGFR1 fusion-transformed hematopoietic cells. Disrupting 14-3-3-ligand association may represent an effective therapeutic strategy to treat 8p11 stem cell MPD.
Wetzler M, Brady MT, Tracy E, et al.Arsenic trioxide affects signal transducer and activator of transcription proteins through alteration of protein tyrosine kinase phosphorylation.
Clin Cancer Res. 2006; 12(22):6817-25 [PubMed
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PURPOSE: Arsenic trioxide decreases proliferation of acute myeloid leukemia (AML) cells, but its precise mechanism of action is unknown.
EXPERIMENTAL DESIGN: We studied the effect of arsenic trioxide on patient samples and the AML cell line HEL, which, like leukemic blasts from 50% of AML cases, has constitutively activated signal transducer and activator of transcription (STAT) proteins.
RESULTS: Arsenic trioxide induced mitotic arrest starting at 24 hours and significant cell death at 48 hours. These events were preceded by an arsenic trioxide dose-dependent down-regulation of activated STAT proteins starting at 6 hours. We hypothesized that arsenic trioxide inhibits protein tyrosine kinases (PTK), which, among others, phosphorylate and activate STATs. We therefore studied arsenic trioxide effects on Janus kinases and on three oncogenic PTKs that are known to activate STATs [FLT3, ZNF198/fibroblast growth factor receptor 1 (FGFR1), and BCR/ABL]. Arsenic trioxide reduced STAT3 activation by Janus kinases, altered phosphorylation and electrophoretic mobility of ZNF198/fibroblast growth factor receptor 1, reduced kinase protein level, and decreased STAT3 protein phosphorylation. Arsenic trioxide also reduced the phosphorylation of BCR/ABL and FLT3 with corresponding decreased STAT5 phosphorylation.
CONCLUSIONS: These results suggest a selective activity of arsenic trioxide on PTKs and will assist in developing clinical trials in AML.