High caspase 3 and vulnerability to dual BCL2 family inhibition define ETO2::GLIS2 pediatric leukemia.

Pediatric acute myeloid leukemia expressing the ETO2::GLIS2 fusion oncogene is associated with dismal prognosis. Previous studies have shown that ETO2::GLIS2 can efficiently induce leukemia development associated with strong transcriptional changes but those amenable to pharmacological targeting remained to be identified. By studying an inducible ETO2::GLIS2 cellular model, we uncovered that de novo ETO2::GLIS2 expression in human cells led to increased CASP3 transcription, CASP3 activation, and cell death. Patient-derived ETO2::GLIS2+ leukemic cells expressed both high CASP3 and high BCL2. While BCL2 inhibition partly inhibited ETO2::GLIS2+ leukemic cell proliferation, BH3 profiling revealed that it also sensitized these cells to MCL1 inhibition indicating a functional redundancy between BCL2 and MCL1. We further show that combined inhibition of BCL2 and MCL1 is mandatory to abrogate disease progression using in vivo patient-derived xenograft models. These data reveal that a transcriptional consequence of ETO2::GLIS2 expression includes a positive regulation of the pro-apoptotic CASP3 and associates with a vulnerability to combined targeting of two BCL2 family members providing a novel therapeutic perspective for this aggressive pediatric AML subgroup.

Aid Z ，Robert E ，Lopez CK ，Bourgoin M ，Boudia F ，Le Mene M ，Riviere J ，Baille M ，Benbarche S ，Renou L ，Fagnan A ，Thirant C ，Federici L ，Touchard L ，Lecluse Y ，Jetten A ，Geoerger B ，Lapillonne H ，Solary E ，Gaudry M ，Meshinchi S ，Pflumio F ，Auberger P ，Lobry C ，Petit A ，Jacquel A ，Mercher T ... -  《-》

Developmental interplay between transcriptional alterations and a targetable cytokine signaling dependency in pediatric ETO2::GLIS2 leukemia.

Alonso-Pérez V ，Galant K ，Boudia F ，Robert E ，Aid Z ，Renou L ，Barroca V ，Devanand S ，Babin L ，Rouiller-Fabre V ，Moison D ，Busso D ，Piton G ，Metereau C ，Abermil N ，Ballerini P ，Hirsch P ，Haddad R ，Martinovic J ，Petit A ，Lapillonne H ，Brunet E ，Mercher T ，Pflumio F ... -  《Molecular Cancer》

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》

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 ... -  《-》

Molecular pathways driven by ETO2-GLIS2 in aggressive pediatric leukemia.

Thirant C ，Lopez C ，Malinge S ，Mercher T ... -  《Molecular & Cellular Oncology》