TEL/ETV6 accelerates erythroid differentiation and inhibits megakaryocytic maturation in a human leukemia cell line UT‐7/GM

Abstract

T EL (also known as ETV6) is a member of the E26 transformation-specific (ETS) family of transcription factors.(1) The highly conserved ETS domain is located at the Cterminal region, while a distinct domain with weak homology to the well-described helix-loop-helix (HLH) domain (also referred to as the pointed domain) is located at the N-terminal region. The former serves for DNA binding to the ETS-binding consensus site (EBS) (GGAA/ T) and the latter for homodimerization and heterodimerization with other ETS family members.(2,3) Through interacting with relevant corepressors mSin3A, N-CoR and SMRT, and histone deacetylase-3, (4) TEL mediates transcriptional repression on its target genes such as FLI-1,inhibitor of differentiation / DNA binding-1 (Id-1), (5) stromelysin-1 (6) and Bcl-X L .(7) Transcriptional activities of TEL are regulated through phosphorylation with mitogen-activated protein kinases (8,9) and small ubiquitin-like modifier conjugation. (10,11) The TEL gene that is mapped to 12p13 is most frequently rearranged and fused to various partner genes by chromosomal translocations in human leukemias and myelodysplastic syndromes. The partners include receptor type or non-receptor type tyrosine kinases and transcription factors. Providing tyrosine kinases, such as platelet-derived growth factor receptor β (PDGFRβ) in t(5;12) (q33;p13), (12) ABL1 in t(9;12) (q34;p13),ARG (ABL2) in t(1;12) (q25;p13), (14) JAK2 in t(9;12) (p24;p13) (15) and Syk in t(9;12) (q22;p13), (16) with the HLH domain, TEL homodimerizes them and thereby stimulates their kinase activities. In contrast, TEL gives corepressor-binding domains to a transcription factor AML1 in t(12;21) (p13;q22) and interferes with its transcriptional abilities.(17) Therefore, dysregulation of the partner proteins by TEL functional domains seems to cause leukemia in patients with 12p13 translocations. Moreover, inactivation of the TEL gene is speculated to be the second hit in t(12;21) (p13;q22) type leukemia, because the wild-type-TEL allele is deleted in the vast majority of the patients. (18,19) Thus, TEL appears to be a tumor suppressor. Consistent with its roles as a putative tumor suppressor, expression of TEL in Ras-transformed NIH3T3 cells inhibits cell growth in liquid and soft agar cultures, (6) and in serum-starved NIH3T3 cells induces apoptosis. (6)

ETV6 in hematopoiesis and leukemia predisposition

“…However, increases in mean erythrocyte volume were reported in a fraction of patients in two studies, raising the possibility that ETV6 plays a non-essential role in erythropoiesis (18, 21). Supporting this notion, over-expression of ETV6 driven by the Gata1 promoter in transgenic mice resulted in subtle increases in hemoglobin (46), and this was consistent with the results of over-expression of ETV6 in cell lines (44, 50). However, as the increases in MCV only occur in a fraction of patients with ETV6 mutations and over-expression of ETV6 may be subject to artifacts from binding non-physiological ETS-sites.…”

“…Over-expression of ETV6 was reported to suppress (29, 44, 45) or enhance (46) the megakaryocyte program different systems, the latter more easy to reconcile with the recent clinical findings. Disruption of ETV6 after the HSC commitment to the megakarycyte/erythroid lineage utilizing Gata1-Cre resulted in consistent, marked reduction of platelet counts (42).…”

Leukemia‐related transcription factor TEL/ETV6 expands erythroid precursors and stimulates hemoglobin synthesis

“…We have previously reported by evaluating Hb accumulation with benzidine staining that overexpressed TEL stimulates erythroid differentiation in UT7/GM and MEL cells. ( 13,14 ) In both the cell lines, expressional levels of β‐globin and ALAS‐E mRNAs were higher in the TEL ‐overexpressing cells. These previous data are consistent with those observed here in the CD71 high /TER119 + population of bone marrow cells in the GATA1‐TEL transgenic mice.…”

ETV6 (TEL1) regulates embryonic hematopoiesis in zebrafish

“…Previous work has shown that selective excision of Etv6 in the erythroid lineage of mice failed to impact on erythropoiesis. 20 However, other data have demonstrated that overexpression of ETV6 enhanced erythroid differentiation in cell models, 49 as well as leading to increased erythroid precursors, accelerated differentiation and augmented globin expression in mice transgenic for ETV6. 21 Our data are consistent with the latter studies, with etv6 morphants showing an initial decrease in gata1 expression, followed by a sustained increase in expression.…”