Evi1 Counteracts Anti-Leukemic and Stem Cell Inhibitory Effects of All-Trans Retinoic Acid on Flt3-ITD/Npm1c-Driven Acute Myeloid Leukemia Cells

Abstract

All-trans retinoic acid (atRA) has a dramatic impact on the survival of patients with acute promyelocytic leukemia, but its therapeutic value in other types of acute myeloid leukemia (AML) has so far remained unclear. Given that AML is a stem cell-driven disease, recent studies have addressed the effects of atRA on leukemic stem cells (LSCs). atRA promoted stemness of MLL-AF9-driven AML in an Evi1-dependent manner but had the opposite effect in Flt3-ITD/Nup98-Hoxd13-driven AML. Overexpression of the stem cell-associated transcription factor EVI1 predicts a poor prognosis in AML, and is observed in different genetic subtypes, including cytogenetically normal AML. Here, we therefore investigated the effects of Evi1 in a mouse model for cytogenetically normal AML, which rests on the combined activity of Flt3-ITD and Npm1c mutations. Experimental expression of Evi1 on this background strongly promoted disease aggressiveness. atRA inhibited leukemia cell viability and stem cell-related properties, and these effects were counteracted by overexpression of Evi1. These data further underscore the complexity of the responsiveness of AML LSCs to atRA and point out the need for additional investigations which may lay a foundation for a precision medicine-based use of retinoids in AML.

CRISPR-mediated MECOM depletion retards tumor growth by reducing cancer stem cell properties in lung squamous cell carcinoma

“…Recently, MECOM was shown to play an essential role in the occurrence and progression of ovarian, colorectal, breast, and lung cancers. [38][39][40][41][42] MECOM reportedly maintained the self-renewal of hematopoietic stem cells 17,18 and promoted CSC properties in acute myeloid leukemia 17,43 and nasopharyngeal carcinoma. 15,44 Consistent with the results of these previous studies, we detected enriched proliferation and stem cell-associated signaling in LUSC cells with the forced expression of MECOM.…”

Therapeutic Use of Valproic Acid and All-Trans Retinoic Acid in Acute Myeloid Leukemia—Literature Review and Discussion of Possible Use in Relapse after Allogeneic Stem Cell Transplantation

“…Experimental studies suggest that the antileukemic effect of ATRA varies between patients [ 4 , 58 ], and this is further supported by clinical studies. A large phase III clinical trial including 242 elderly patients above 60 years of age described higher response rates and better event-free as well as overall survival in patients receiving ATRA together with conventional intensive induction and first consolidation chemotherapy [ 59 ].…”

“… FLT3 -ITD. Studies in an animal model of FLT3 -ITD/NPM1c-driven AML suggest that ATRA has an antileukemic effect in this AML model through effects on leukemic stem cells, but this pharmacological effect is counteracted by experimental expression of the stem cell-associated transcription factor EVI1 [ 58 ]. NPM1 mutations.…”

“…This gene encodes a stem cell-associated transcription factor that is downregulated during hematopoietic differentiation. High expression is observed for 10% of AML patients and is associated with an adverse prognosis [ 58 , 71 , 72 , 73 ]. This factor is upregulated by ATRA [ 74 , 75 , 76 ], and high EVI1 levels seem to enhance the transcriptional response to ATRA [ 77 ], thereby causing differentiation induction, decreased clonogenic proliferation, and decreased AML engraftment in immunocompromised mice [ 78 ].…”

“…These antileukemic effects seem to be caused by the effects of ATRA on the AML stem cells for patients with stem cell-derived leukemia and therefore high EVI1 expression, but the effect is weak or absent in AML derived from progenitor cell transformation and shows low EVI1 expression [ 79 ]. However, this effect of EVF1 expression is probably more complex because it may be further modulated by other genetic abnormalities [ 58 ].…”