Purpose: The resistance to differentiation therapy and early death caused by fatal bleeding endangers the health of a significant proportion of patients with acute promyelocytic leukemia (APL). This study aims to investigate the molecular mechanisms of all-trans retinoic acid (ATRA) resistance and uncover new potential therapeutic strategies to block the rapid progression of early death. Experimental Design: The important role of TWIST1 in APL leukemogenesis was first determined by gain-and lossof-function assays. We then performed in vivo and in vitro experiments to explore the interaction of TWIST1 and TRIB3 and develop a potential peptide-initiated therapeutic opportunity to protect against early death and induction therapy resistance in patients with APL. Results: We found that the epithelial-mesenchymal transition (EMT)-inducing transcription factor TWIST1 is highly expressed in APL cells and is critical for leukemic cell survival. TWIST1 and TRIB3 were highly coexpressed in APL cells compared with other subtypes of acute myeloid leukemia cells. We subsequently demonstrated that TRIB3 could bind to the WR domain of TWIST1 and contribute to its stabilization by inhibiting its ubiquitination. TRIB3 depletion promoting TWIST1 degradation reverses resistance to induction therapy and improves sensitivity to ATRA. On the basis of a detailed functional screen of synthetic peptides, we discovered a peptide analogous to the TWIST1 WR domain that specifically represses APL cell survival by disrupting the TRIB3/TWIST1 interaction. Conclusions: Our data not only define the essential role of TWIST1 as an EMT-TF in patients with APL but also suggest that disrupting the TRIB3/TWIST1 interaction reverses induction therapy resistance and blocks rapid progression of APL early death. See related commentary by Peeke and Gritsman, p. 6018

Secreted proteins provide crucial signals that have been implicated in the development of acute myeloid leukemia (AML) in the bone marrow microenvironment. Here we identify aberrant expressions of inflammatory IL‐17B and its receptor (IL‐17RB) in human and mouse mixed lineage leukemia–rearranged AML cells, which were further increased after exposure to chemotherapy. Interestingly, silencing of IL‐17B or IL‐17RB led to significant suppression of leukemic cell survival and disease progression in vivo. Moreover, the IL‐17B–IL‐17RB axis protected leukemic cells from chemotherapeutic agent–induced apoptotic effects. Mechanistic studies revealed that IL‐17B promoted AML cell survival by enhancing ERK, NF‐κB phosphorylation, and the expression of antiapoptotic protein B‐cell lymphoma 2, which were reversed by small‐molecule inhibitors. Thus, the inhibition of the IL‐17B–IL‐17RB axis may be a valid strategy to enhance sensitivity and therapeutic benefit of AML chemotherapy.—Guo, H.‐Z., Niu, L.‐T., Qiang, W.‐T., Chen, J., Wang, J., Yang, H., Zhang, W., Zhu, J., Yu, S.‐H. Leukemic IL‐17RB signaling regulates leukemic survival and chemoresistance. FASEB J. 33, 9565–9576 (2019). http://www.fasebj.org

No abstract