Abstract
Stabilization of MLL fusions through proteasome inhibition induces pro-B MLL leukemia cell death.
Major finding: Stabilization of MLL fusions through proteasome inhibition induces pro-B MLL leukemia cell death.
Clinical relevance: Bortezomib showed activity in two patients with pro-B MLL leukemia.
Impact: Oncogenes with latent tumor-suppressive properties may be exploitable for treatment strategies.
Translocations involving the mixed-lineage leukemia (MLL) gene induce aggressive leukemias, but high expression of MLL fusion proteins is rarely observed, suggesting that accumulation of MLL fusion products may negatively affect leukemia cell survival. Liu and colleagues found that MLL and MLL fusion protein accumulation increased upon proteasome inhibition in human leukemia cell lines and that the proteasome inhibitors bortezomib and carfilzomib caused a significant dose-dependent reduction in viability specifically in progenitor B-cell (pro-B) leukemia cells with MLL fusions but not pro-B non-MLL leukemias or MLL fusion-positive myeloid leukemias. Bortezomib-induced cell death in pro-B MLL leukemia cells was dependent on MLL fusion protein accumulation, as death was prevented by MLL fusion protein depletion and overexpression of MLL fusion proteins in non-MLL pro-B leukemia lines increased sensitivity to proteasome inhibition. Mechanistically, bortezomib activated a mitochondrial apoptotic pathway in pro-B MLL leukemia cells through upregulation of caspase 8 that led to the cleavage and activation of pro-apoptotic BID. In addition to apoptosis, bortezomib treatment also induced a potent cell-cycle arrest in G2/M that was dependent on induction of the p27 gene CDKN1B by bortezomib-stabilized MLL fusion proteins, which promoted transcription via recruitment of the positive transcription elongation factor b complex and interaction with the B cell-specific transcription factor PAX5. Bortezomib treatment significantly inhibited pro-B MLL leukemia tumor progression in a mouse xenograft model, providing evidence that proteasome inhibitors have activity against pro-B MLL leukemia in vivo. Based on these findings, 5 adult patients with MLL leukemia received bortezomib through compassionate use. Consistent with the preclinical findings, responses were only observed in the patients with pro-B leukemia; one patient had a complete remission lasting longer than 1 year. Taken together, these results indicate that exploitation of latent tumor-suppressive properties of oncogenes could be effective in cancer treatment, particularly for pro-B MLL leukemias.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.