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》

New hPSC-based human models to study pediatric Acute Megakaryoblastic Leukemia harboring the fusion oncogene RBM15-MKL1.

Pediatric Acute Megakaryoblastic Leukemia not associated to Down Syndrome (non-DS AMKL) is a rare disease with a dismal prognosis. Around 15% of patients carry the chromosomal translocation t(1;22) that originates the fusion oncogene RBM15-MKL1, which is linked to an earlier disease onset (median of 6months of age) and arises in utero. Here we report the generation of two hPSC cell lines constitutively expressing the oncogene RBM15-MKL1, resulting in an increased expression of known RBM15-MKL1 gene targets. These cell lines represent new disease models of pediatric AMKL to study the impact of the RBM15-MKL1 oncogene on human embryonic hematopoietic development.

Ayllón V ，Vogel-González M ，González-Pozas F ，Domingo-Reinés J ，Montes R ，Morales-Cacho L ，Ramos-Mejía V ... -  《-》

[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 《-》

The OTT-MAL fusion oncogene activates RBPJ-mediated transcription and induces acute megakaryoblastic leukemia in a knockin mouse model.

Mercher T ，Raffel GD ，Moore SA ，Cornejo MG ，Baudry-Bluteau D ，Cagnard N ，Jesneck JL ，Pikman Y ，Cullen D ，Williams IR ，Akashi K ，Shigematsu H ，Bourquin JP ，Giovannini M ，Vainchenker W ，Levine RL ，Lee BH ，Bernard OA ，Gilliland DG ... -  《-》

miR-125b-2 is a potential oncomiR on human chromosome 21 in megakaryoblastic leukemia.

Klusmann JH ，Li Z ，Böhmer K ，Maroz A ，Koch ML ，Emmrich S ，Godinho FJ ，Orkin SH ，Reinhardt D ... -  《-》