In myelodysplastic syndromes (MDS), deletions of chromosome 7 or 7q are common and correlate with a poor prognosis. The relevant genes on chromosome 7 are unknown. We report here that EZH2, located at 7q36.1, is frequently targeted in MDS. Analysis of EZH2 deletions, missense and frameshift mutations strongly suggests that EZH2 is a tumor suppressor. As EZH2 functions as a histone methyltransferase, abnormal histone modification may contribute to epigenetic deregulation in MDS.
IntroductionGranulocytes and monocytes develop from common myeloid progenitor cells through a complex network of cell growth, differentiation, and apoptosis-regulating factors. Alterations in these processes may cause acute myeloid leukemia, which is characterized by uncontrolled proliferation of immature myeloid cells that fail to differentiate toward mature functional cells. 1,2 In leukemia, mutations occur in genes encoding tyrosine kinases such as Fms-like tyrosine kinase 3 (Flt3), c-kit, neuroblastoma ras (N-ras) and transcription factors such as AML1 (acute myeloid leukemia 1), CBFB (core binding factor ), GATA1 (GATA binding protein 1), PU.1, C/EBP␣ (CCAAT/enhancer binding protein ␣), and RAR␣ (retinoic acid receptor ␣). 1,2 Although the transcription factors predominantly play a role in lineage commitment, activation of tyrosine kinases is thought to result in proliferative and/or survival signals. 1,2 Recent studies have shown that several proteins involved in myelopoiesis (including proteins mutated in leukemia) are inactivated through ubiquitin (Ub)-proteasomal degradation pathways. [3][4][5][6][7] This form of targeted protein degradation is accomplished by the covalent conjugation of Ub to substrate proteins, usually in the form of a multi-Ub chain, which marks these proteins for progressive degradation by the 26S proteasome. 8,9 Protein ubiquitination is catalyzed through a cascade of reactions. Ub is first activated by the adenosine triphosphate (ATP)-dependent Ub-activating E1 enzyme and subsequently transferred to one of a set of E2 Ub-conjugating enzymes. The E2 enzymes act in conjunction with accessory E3 Ub protein ligases. In the E2-E3 complex, the E3 component binds to protein substrates, allowing the E2 to form a multi-Ub chain linked to a lysine of the substrate protein. 8,9 Thus, the E3 Ub ligases play a crucial role in this process because these proteins recognize the cellular proteins destined for ubiquitination. 10 To date, several types of E3 Ub ligases have been described. These include HECT (homologous to E6-AP carboxyl terminus), RING (really interesting new gene) finger, U-box, SOCS (suppressor of cytokine signaling)-box, F-box, and cullin ligases. [11][12][13][14][15][16][17][18][19][20] Although the first 3 types of proteins are actively involved in substrate ubiquitination, the last 3 do not ubiquitinate substrate proteins themselves but are part of larger protein complexes that exhibit Ub ligase activity. [15][16][17][18][19] From the Central Hematology Laboratory, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; the Department of Hematology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; the Institute of Hematology, Erasmus University Medical Center Rotterdam, The Netherlands. The online version of the article contains a data supplement.Reprints: Bert A. van der Reijden, Central Hematology Laboratory, University Medical Center Nijmegen, PO BOX 9101, 6500 HB Nijmegen, The Netherlands; e-mail: b.vanderreijden@chl.umcn.nl.The publi...
Mutations in the transcription factor NF-E2 in patients with myeloproliferative neoplasms result in a truncated protein that enhances the function of wild-type NF-E2 and causes erythrocytosis and throbocytosis in a mouse model.
Acute promyelocytic leukemia (APL) is uniquely sensitive to treatment with all-trans retinoic acid (ATRA), which results in the expression of genes that induce the terminal granulocytic differentiation of the leukemic blasts. Here we report the identification of two ATRA responsive genes in APL cells, ID1 and ID2. These proteins act as antagonists of basic helix-loophelix (bHLH) transcription factors. ATRA induced a rapid increase in ID1 and ID2, both in the APL cell line NB4 as well as in primary patient cells. In addition, a strong downregulation of E2A was observed. E2A acts as a general heterodimerization partner for many bHLH proteins that are involved in differentiation control in various tissues. The simultaneous upregulation of ID1 and ID2, and the downregulation of E2A suggest a role for bHLH proteins in the induction of differentiation of APL cells following ATRA treatment. To test the relevance of this upregulation, ID1 and ID2 were overexpressed in NB4 cells. Overexpression inhibited proliferation and induced a G0/G1 accumulation. These results indicate that ID1 and ID2 are important retinoic acid responsive genes in APL, and suggest that the inhibition of specific bHLH transcription factor complexes may play a role in the therapeutic effect of ATRA in APL.
Until recently, the genetic aberrations that are causally linked to the pathogenesis of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms were largely unknown. Using novel technologies like high-resolution SNP-array analysis and next generation sequencing, various genes have now been identified that are recurrently mutated. Strikingly, several of the newly identified genes (ASXL1, DNMT3A, EZH2, IDH1 and IDH2, and TET2) are involved in the epigenetic regulation of gene expression. Aberrant epigenetic modifications have been described in many types of cancer, including myeloid malignancies. It has been proposed that repression of genes that are crucial for the cessation of the cell cycle and induction of differentiation might contribute to the malignant transformation of normal hematopoietic cells. Several therapies that aim to re-express silenced genes are currently being tested in MDS, like histone deacetylase inhibitors and hypomethylating agents. It will be interesting to assess whether patients carrying mutations in epigenetic regulators respond differently to these novel forms of epigenetic therapies.
IntroductionAcute promyelocytic leukemia (APL) is characterized by an excess of immature promyelocytes in the bone marrow that fail to differentiate toward mature granulocytes. In approximately 98% of the cases, the retinoic acid receptor-␣ (RAR␣) gene is fused to the promyelocytic leukemia (PML) gene resulting in a PML-RAR␣ fusion protein. The PML-RAR␣ chimeric protein contains most of the PML sequence and a large part of RAR␣, including its DNAand nuclear hormone-binding domains. APL blasts can be forced to terminally differentiate using pharmacological doses of all-trans retinoic acid (ATRA). When treated with chemotherapy, APL patients can be cured in approximately 40% of the cases. The combination of ATRA with chemotherapy leads to a remarkably high cure rate of approximately 90%, 1,2 and APL currently represents the best prognostic group among the different forms of leukemia. This treatment constitutes one of the first examples of successful induction of differentiation of malignant cells yielding significant clinical results.The role of PML-RAR␣ in transformation and terminal differentiation has been studied intensively in the past decade. PML-RAR␣ was shown to act as a dominant oncogene, interfering with the normal function of the unrearranged PML as well as the unrearranged RAR␣ protein. Expression of the fusion protein in immature hematopoietic cells induced a maturation block at the promyelocytic stage. Inoculation of PML-RAR␣-transduced bone marrow cells into irradiated syngenic mice resulted in the development of retinoic acid-sensitive leukemia. 3,4 Furthermore, PML-RAR␣ transgenic mice developed a myeloproliferative syndrome that progressed to overt leukemia in 30% to 90% of the animals after 6 to 12 months, depending on the promoter that was used. [5][6][7] PML is a ubiquitously expressed protein that localizes to nuclear substructures termed nuclear bodies. More than 50 protein partners with various biologic functions colocalize with PML. 8 In APL cells, these nuclear bodies are disrupted and dispersed into numerous small microspeckles. 9 PML has multiple tumorsuppressor functions and is involved in growth control, replicative senescence, and apoptosis. 10 PML Ϫ/Ϫ mice are prone to develop tumors in response to various forms of stress. In addition, PML-RAR␣ transgenic mice develop leukemia much faster in a PML Ϫ/Ϫ background. 11 Retinoic acid receptors are transcription factors that activate genes in a ligand-dependent manner. RAR␣ binds to DNA as a heterodimer with RXR proteins. In the absence of ligand, both RAR␣/RXR and PML-RAR␣ bind corepressors such as N-Cor and SMRT and recruit histone deacetylases leading to gene silencing. In the presence of ligand, the corepressors are replaced by coactivators, leading to transcriptional activation. However, PML-RAR␣ releases the corepressors at much higher concentrations of ligand compared with the unrearranged receptors. Since PML-RAR␣ competes with unrearranged receptors for the same DNAbinding sites, the presence of the fusion protein results in dom...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.