MLL-AF9 Expression in Hematopoietic Stem Cells Drives a Highly Invasive AML Expressing EMT-Related Genes Linked to Poor Outcome

Abstract

To address the impact of cellular origin on acute myeloid leukemia (AML), we generated an inducible transgenic mouse model for MLL-AF9-driven leukemia. MLL-AF9 expression in long-term hematopoietic stem cells (LT-HSC) in vitro resulted in dispersed clonogenic growth and expression of genes involved in migration and invasion. In vivo, 20% LT-HSC-derived AML were particularly aggressive with extensive tissue infiltration, chemoresistance, and expressed genes related to epithelial-mesenchymal transition (EMT) in solid cancers. Knockdown of the EMT regulator ZEB1 significantly reduced leukemic blast invasion. By classifying mouse and human leukemias according to Evi1/EVI1 and Erg/ERG expression, reflecting aggressiveness and cell of origin, and performing comparative transcriptomics, we identified several EMT-related genes that were significantly associated with poor overall survival of AML patients.

Eya2, a Target Activated by Plzf, Is Critical for PLZF-RARA-Induced Leukemogenesis

“…This finding is consistent with findings that knockdown of EMT-related genes suppresses leukemogenesis (41). Surprisingly, Eya2 depletion also reduced the clonogenicity of PML-RARA-immortalized myeloid progenitor cells.…”

RUNX1-ETO and RUNX1-EVI1 Differentially Reprogram the Chromatin Landscape in t(8;21) and t(3;21) AML

“…RUNX1-EVI1 appears to directly regulate a stem cell program establishing an immature phenotype associated with treatment resistance, (Eppert et al., 2011), expressing genes ( MSI2 and ZEB1 ) regulating leukemia aggressiveness (Ito et al., 2010, Stavropoulou et al., 2016). Furthermore, HOXA9 and MEIS1 are both expressed in t(3;21), but not in t(8;21), AML.…”

From EMT to HSC to AML: ZEB2 is a cell fate switch

“…1,7 Fifth, the preliminary data from a few small studies suggest that both PI and non-PI-based regimens are effective in WM, irrespective of the MYD88 mutation status 5,8 ; in contrast, the activity of ibrutinib is primarily confined to the MYD88 mutant subpopulation. The EMN study did not delineate outcome on the basis of the patients' MYD88 mutation status, nor could the patients be longitudinally evaluated for clonal evolution, a phenomenon that has recently been documented in WM with both PI-based and Bruton tyrosine kinase inhibitor-based therapies.…”

“…In agreement with these findings, another recent study identified invasion, migration, and metastasis genes, including Zeb2, associated with aggressive, early-onset, HSCderived AML, which were not present in slower-growing, more differentiated, progenitor-derived AML. 8 Altogether, these studies remind us of the complexity of balancing stemness and differentiation with many other processes such as migration, invasion, and proliferation in hematopoiesis and leukemia. But is ZEB2 a master "on/off" switch that integrates all these processes?…”