A direct comparison between AML1-ETO and ETO2-GLIS2 leukemia fusion proteins reveals context-dependent binding and regulation of target genes and opposite functions in cell differentiation.

The ETO-family transcriptional corepressors, including ETO, ETO2, and MTGR1, are all involved in leukemia-causing chromosomal translocations. In every case, an ETO-family corepressor acquires a DNA-binding domain (DBD) to form a typical transcription factor-the DBD binds to DNA, while the ETO moiety manifests transcriptional activity. A directly comparative study of these "homologous" fusion transcription factors may clarify their similarities and differences in regulating transcription and leukemogenesis. Here, we performed a side-by-side comparison between AML1-ETO and ETO2-GLIS2, the most common fusion proteins in M2-and M7-subtypes of acute myeloid leukemia, respectively, by inducible expression of them in U937 leukemia cells. We found that, although AML1-ETO and ETO2-GLIS2 can use their own DBDs to bind DNA, they share a large proportion of genome-wide binding regions dependent on other cooperative transcription factors, including the ETS-, bZIP- and bHLH-family proteins. AML1-ETO acts as either transcriptional repressor or activator, whereas ETO2-GLIS2 mainly acts as activator. The repressor-versus-activator functions of AML1-ETO might be determined by the abundance of cooperative transcription factors/cofactors on the target genes. Importantly, AML1-ETO and ETO2-GLIS2 differentially regulate key transcription factors in myeloid differentiation including PU.1 and C/EBPβ. Consequently, AML1-ETO inhibits, but ETO2-GLIS2 facilitates, myeloid differentiation of U937 cells. This function of ETO2-GLIS2 is reminiscent of a similar effect of MLL-AF9 as previously reported. Taken together, this directly comparative study between AML1-ETO and ETO2-GLIS2 in the same cellular context provides insights into context-dependent transcription regulatory mechanisms that may underlie how these seemingly "homologous" fusion transcription factors exert distinct functions to drive different subtypes of leukemia.

Zhang YF ，Wang XL ，Xu CH ，Liu N ，Zhang L ，Zhang YM ，Xie YY ，Zhang YL ，Huang QH ，Wang L ，Chen Z ，Chen SJ ，Roeder RG ，Shen S ，Xue K ，Sun XJ ... -  《Frontiers in Cell and Developmental Biology》

The myeloid master regulator transcription factor PU.1 is inactivated by AML1-ETO in t(8;21) myeloid leukemia.

Vangala RK ，Heiss-Neumann MS ，Rangatia JS ，Singh SM ，Schoch C ，Tenen DG ，Hiddemann W ，Behre G ... -  《BLOOD》

ETO2-GLIS2 Hijacks Transcriptional Complexes to Drive Cellular Identity and Self-Renewal in Pediatric Acute Megakaryoblastic Leukemia.

Chimeric transcription factors are a hallmark of human leukemia, but the molecular mechanisms by which they block differentiation and promote aberrant self-renewal remain unclear. Here, we demonstrate that the ETO2-GLIS2 fusion oncoprotein, which is found in aggressive acute megakaryoblastic leukemia, confers megakaryocytic identity via the GLIS2 moiety while both ETO2 and GLIS2 domains are required to drive increased self-renewal properties. ETO2-GLIS2 directly binds DNA to control transcription of associated genes by upregulation of expression and interaction with the ETS-related ERG protein at enhancer elements. Importantly, specific interference with ETO2-GLIS2 oligomerization reverses the transcriptional activation at enhancers and promotes megakaryocytic differentiation, providing a relevant interface to target in this poor-prognosis pediatric leukemia.

Thirant C ，Ignacimouttou C ，Lopez CK ，Diop M ，Le Mouël L ，Thiollier C ，Siret A ，Dessen P ，Aid Z ，Rivière J ，Rameau P ，Lefebvre C ，Khaled M ，Leverger G ，Ballerini P ，Petit A ，Raslova H ，Carmichael CL ，Kile BT ，Soler E ，Crispino JD ，Wichmann C ，Pflumio F ，Schwaller J ，Vainchenker W ，Lobry C ，Droin N ，Bernard OA ，Malinge S ，Mercher T ... -  《-》

Different roles of E proteins in t(8;21) leukemia: E2-2 compromises the function of AETFC and negatively regulates leukemogenesis.

Liu N ，Song J ，Xie Y ，Wang XL ，Rong B ，Man N ，Zhang MM ，Zhang Q ，Gao FF ，Du MR ，Zhang Y ，Shen J ，Xu CH ，Hu CL ，Wu JC ，Liu P ，Zhang YL ，Xie YY ，Liu P ，Huang JY ，Huang QH ，Lan F ，Shen S ，Nimer SD ，Chen Z ，Chen SJ ，Roeder RG ，Wang L ，Sun XJ ... -  《-》

New insights into transcriptional and leukemogenic mechanisms of AML1-ETO and E2A fusion proteins.

Li J ，Guo C ，Steinauer N ，Zhang J ... -  《-》