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

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.

Deubiquitinating Enzyme Inhibitor Alleviates Cyclin A1-mediated Proteasome Inhibitor Tolerance in Mixed-lineage Leukemia

“…3d, e). In addition, consistent with a critical role in the drugresistance and DNA-damage responses, 19,22,44 reduction of MLL in PI-tolerant cells was associated with an increase in histone γ-H2AX (Fig. 3e).…”

“…18 However, the inevitable emergence of PI resistance limits the clinical application of bortezomib. 19,20 There is thus a need to identify the mechanism underlying PI resistance and to design novel combination strategies to overcome resistance and promote the application of PIs for MLL leukemias.…”

“…20 The remaining drug-tolerant cells eventually acquire resistance through PI-induced epigenetic reprogramming and subsequent loss of MLL protein function and cell cycle deregulation. 19 However, little is known about how MLL cells orchestrate their cell cycle adaptive response under PI challenge.…”

“…PI treatment induces remodeling of histone H2B monoubiquitination (H2Bub). 19,30 H2Bub depletion could impair the recruitment of MLL to chromatin and H3K4 methylation. [31][32][33] The crosstalk between H2Bub and MLL-mediated H3K4 methylation also affects the expression of cell cycle genes.…”

mTORC1‐mediated amino acid signaling is critical for cell fate determination under transplant‐induced stress

“…Transplantation of in vitro-manipulated cells is a widely used and powerful procedure in basic research and translational studies in the field of hematology. For example, cell line-derived xenograft mouse models are essential in studying the pathogenesis of diseases, testing the efficacy of treatment, and investigating molecular mechanisms of therapeutic resistance [1][2][3]. Ex vivo human hematopoietic stem cell (HSC) expansion and generating HSCs through in vitro reprogramming constitute a new hope for solving the issue of HSC shortage [4,5].…”