Overexpression of Mdmx hastened leukemogenesis by upregulating WNT–β-catenin signaling in vivo
Major Finding: Overexpression of Mdmx hastened leukemogenesis by upregulating WNT–β-catenin signaling in vivo.
Concept: Binding of MDMX to CK1α sequestered CK1α from β-catenin, preventing β-catenin degradation.
Impact: This study pinpoints MDMX as a critical factor promoting the transition to acute myeloid leukemia.
In the majority of patients with acute myeloid leukemia (AML), leukemic cells do not harbor mutations in TP53 (encoding p53). Instead, p53 suppression in AML occurs via overexpression of MDMX (also known as MDM4), a nuclear protein that inhibits p53 by binding p53's transcriptional activation domain and by stabilizing the p53 degrader MDM2. Ueda, Kumari, Schwenger, and colleagues sought to gain a deeper understanding of the effects of MDMX overexpression during normal hematopoiesis and leukemogenesis. In vivo, overexpression of Mdmx in hematopoietic stem cells (HSC) led to faster HSC proliferation and competitiveness (as assessed by functional repopulating capacity in congenic transplantation experiments). Further, in mice underexpressing Spi1 (encoding the transcription factor PU.1), a tumor suppressor gene whose loss of function leads to preleukemic states in mice and humans, Mdmx overexpression led to a transition from a preleukemic state to overt AML. In an additional mouse model system with Tet2 loss-of-function mutations affecting one or both copies of the gene (leading to clonal hematopoiesis or myeloproliferative neoplasms and myelodysplastic syndrome, respectively)—a common feature of early human progression to AML—Mdmx overexpression caused a transition to overt AML. Further, in mice harboring a single copy of Flt3 with an internal tandem duplication (ITD), mimicking this AML-predisposing mutation in humans, the Flt3 ITD mutation alone was not sufficient to cause AML, but promoted AML development upon Mdmx overexpression. Mechanistically, Mdmx overexpression caused upregulation of WNT–β-catenin signaling in hematopoietic stem cells via MDMX–casein kinase 1α (CK1α) binding, sequestering CK1α from β-catenin and thus preventing both β-catenin phosphorylation at S45 and phosphorylation-dependent degradation of β-catenin. In agreement with the proposed mechanism, inhibitors of WNT–β-catenin signaling prevented the leukemia-promoting effects of Mdmx overexpression and exhibited synergy with MDMX–p53 inhibitors. In summary, this work identifies MDMX as a key factor promoting the transition from preleukemic states to AML and provides mechanistic insight that may yield useful drug targets.
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