Restoring MLL reactivates latent tumor suppression-mediated vulnerability to proteasome inhibitors

Maolin Ge,Zhi Qiao,Shouhai Zhu,Zhenshu Xu,Shifen Wang,Ting Kang,Yan Sun,Chunjun Zhao,Dan Li,Shuhong Shen,Han Liu,Hua Xiao

doi:10.1038/s41388-020-01408-7

Abstract

MLL undergoes multiple distinct chromosomal translocations to yield aggressive leukemia with dismal outcomes. Besides their well-established role in leukemogenesis, MLL fusions also possess latent tumor-suppressive activity, which can be exploited as effective cancer treatment strategies using pharmacological means such as proteasome inhibitors (PIs). Here, using MLL-rearranged xenografts and MLL leukemic cells as models, we show that wild-type MLL is indispensable for the latent tumor-suppressive activity of MLL fusions. MLL dysfunction, shown as loss of the chromatin accumulation and subsequent degradation of MLL, compromises the latent tumor suppression of MLL-AF4 and is instrumental for the acquired PI resistance. Mechanistically, MLL dysfunction is caused by chronic PI treatment-induced epigenetic reprogramming through the H2Bub-ASH2L-MLL axis and can be specifically restored by histone deacetylase (HDAC) inhibitors, which induce histone acetylation and recruits MLL on chromatin to promote cell cycle gene expression. Our findings not only demonstrate the mechanism underlying the inevitable acquisition of PI resistance in MLL leukemic cells, but also illustrate that preventing the emergence of PI-resistant cells constitutes a novel rationale for combination therapy with PIs and HDAC inhibitors in MLL leukemias.

Highlights

The mixed-lineage leukemia (MLL) gene encodes a histone methyltransferase governing histone H3 lysine residue 4These authors contributed : Maolin Ge, Dan Li, Zhi Qiao, Yan Sun
We previously observed that pro-B MLL leukemia displayed selective sensitivity to the proteasome inhibitors (PIs) bortezomib, but the disease did eventually develop in xenograft mice [18]
In PI-sensitive MLL leukemic cells, bortezomib induces the accumulation of MLL-AF4 and latent tumor suppression programs, triggering cell cycle arrest involving the activation of the p27 gene (CDKN1B) [18]

Summary

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The mixed-lineage leukemia (MLL) gene encodes a histone methyltransferase governing histone H3 lysine residue 4. Other studies have demonstrated that endogenous MLL is dispensable for MLL-rearranged AML and that MLL deletion alone had no major impact on the survival of MLL leukemic cells [12, 13] These discrepancies occur mainly in AML models, while the contribution of the wild-type allele of MLL to MLL-rearranged ALL remains elusive. IRAK and CKII inhibition induce wild-type MLL to outcompete the oncogenic MLL chimeras through additional chromatin-binding modules, such as PHD fingers and a bromodomain. These domains are not retained in MLL fusions but exist exclusively in wild-type MLL [16]. We reasoned that disruption of the balance between wild-type MLL and MLL chimeras plays a critical role in PI resistance, and that targeting MLL dysfunction and restoring MLL may be a promising strategy for treating the aggressive resistance in MLL leukemia

Results

Discussion

Materials and methods

Compliance with ethical standards