Abstract
SummaryThe transcription factor Meis1 drives myeloid leukemogenesis in the context of Hox gene overexpression but is currently considered undruggable. We therefore investigated whether myeloid progenitor cells transformed by Hoxa9 and Meis1 become addicted to targetable signaling pathways. A comprehensive (phospho)proteomic analysis revealed that Meis1 increased Syk protein expression and activity. Syk upregulation occurs through a Meis1-dependent feedback loop. By dissecting this loop, we show that Syk is a direct target of miR-146a, whose expression is indirectly regulated by Meis1 through the transcription factor PU.1. In the context of Hoxa9 overexpression, Syk signaling induces Meis1, recapitulating several leukemogenic features of Hoxa9/Meis1-driven leukemia. Finally, Syk inhibition disrupts the identified regulatory loop, prolonging survival of mice with Hoxa9/Meis1-driven leukemia.
Highlights
Acute myeloid leukemia (AML) is an aggressive neoplastic disease characterized by enhanced proliferation, blocked differentiation, and dysregulated apoptosis
We investigated whether myeloid progenitor cells transformed by Hoxa9 and Meis1 become addicted to targetable signaling pathways
We show that Syk is a direct target of miR-146a, whose expression is indirectly regulated by Meis1 through the transcription factor PU.1
Summary
Acute myeloid leukemia (AML) is an aggressive neoplastic disease characterized by enhanced proliferation, blocked differentiation, and dysregulated apoptosis. AML appears to be driven by cell populations exhibiting extensive self-renewal properties, known as leukemia stem cells (LSCs). Despite an increased understanding of the genetic mutations driving the development of AML, the molecular processes that govern these self-renewal properties remain elusive (The Cancer Genome Atlas Research Network, 2013). Subsets of AML with favorable genetic features, such as core-binding factor leukemias and PML-RARa-positive leukemias, express low levels of Hox genes (Drabkin et al, 2002; Lawrence et al, 1999; Valk et al, 2004). Unfavorable genetic alterations, such as mixed-lineage leukemia (MLL) fusions (for instance MLL-AF9 and MLL-ENL) exhibit their transforming capacity largely through upregulation of Hox genes (Krivtsov and Armstrong, 2007; Muntean and Hess, 2012)
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