[Pediatric de novo acute megakaryoblastic leukemia: an affair of complexes].

Pediatric acute megakaryoblastic leukemia (AMKL) are generally associated with poor prognosis and the expression of fusion oncogenes involving transcriptional regulators. Recent results indicate that the ETO2-GLIS2 fusion, associated with 25-30 % of pediatric AMKL, binds and alters the activity of regulatory regions of gene expression, called "enhancers", resulting in the deregulation of GATA and ETS factors essential for the development of hematopoietic stem cells. An imbalance in GATA/ETS factor activity is also found in other AMKL subgroups. This review addresses the transcriptional bases of transformation in pediatric AMKL and therapeutic perspectives.

Lopez CK ，Mercher T 《-》

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 ... -  《-》

CBFA2T3-GLIS2-dependent pediatric acute megakaryoblastic leukemia is driven by GLIS2 and sensitive to navitoclax.

Pediatric acute megakaryoblastic leukemia (AMKL) is an aggressive blood cancer associated with poor therapeutic response and high mortality. Here we describe the development of CBFA2T3-GLIS2-driven mouse models of AMKL that recapitulate the phenotypic and transcriptional signatures of the human disease. We show that an activating Ras mutation that occurs in human AMKL increases the penetrance and decreases the latency of CBF2AT3-GLIS2-driven AMKL. CBFA2T3-GLIS2 and GLIS2 modulate similar transcriptional networks. We identify the dominant oncogenic properties of GLIS2 that trigger AMKL in cooperation with oncogenic Ras. We find that both CBFA2T3-GLIS2 and GLIS2 alter the expression of a number of BH3-only proteins, causing AMKL cell sensitivity to the BCL2 inhibitor navitoclax both in vitro and in vivo, suggesting a potential therapeutic option for pediatric patients suffering from CBFA2T3-GLIS2-driven AMKL.

Neault M ，Lebert-Ghali CÉ ，Fournier M ，Capdevielle C ，Garfinkle EAR ，Obermayer A ，Cotton A ，Boulay K ，Sawchyn C ，St-Amand S ，Nguyen KH ，Assaf B ，Mercier FE ，Delisle JS ，Drobetsky EA ，Hulea L ，Shaw TI ，Zuber J ，Gruber TA ，Melichar HJ ，Mallette FA ... -  《Cell Reports》

Pediatric Acute Megakaryoblastic Leukemia: Multitasking Fusion Proteins and Oncogenic Cooperations.

Pediatric leukemia presents specific clinical and genetic features from adult leukemia but the underpinning mechanisms of transformation are still unclear. Acute megakaryoblastic leukemia (AMKL) is the malignant accumulation of progenitors of the megakaryocyte lineage that normally produce blood platelets. AMKL is diagnosed de novo, in patients showing a poor prognosis, or in Down syndrome (DS) patients with a better prognosis. Recent data show that de novo AMKL is primarily associated with chromosomal alterations leading to the expression of fusions between transcriptional regulators. This review highlights the most recurrent genetic events found in de novo pediatric AMKL patients and, based on recent functional analyses, proposes a mechanism of leukemogenesis common to de novo and DS-AMKL.

Lopez CK ，Malinge S ，Gaudry M ，Bernard OA ，Mercher T ... -  《Trends in Cancer》

[Prognostic significance of chimeric fusion gene analysis in pediatric acute megakaryoblastic leukemia].

Tamefusa K ，Fukutake K ，Ishida H ，Tamura A ，Endo M ，Hamamoto K ，Koga Y ，Yamada M ，Kanamitsu K ，Fujiwara K ，Washio K ，Shimada A ... -  《-》