A novel targeted therapy against acute myeloid leukemia
A new study from Academia Sinica revealed a novel potential target, SCUBE1, for immunotherapy in MLL-rearranged (MLL-r) leukemia. This study was published in “Haematologica” in August, 2022.
Rearrangement of the mixed lineage leukemia gene (MLL) on chromosomal band 11q23 accounts for 10% of all human leukemias and manifests as acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). Although conventional chemotherapy has been improved for leukemia, patients with MLL-rearranged (MLL-r) leukemia generally exhibit relatively poor treatment response and poor prognosis. Our study shows that gene expression of SCUBE1 is highly upregulated in MLL-r leukemia and predicts poor prognosis in de novo AML. We further use a conditional knockout mouse model that Scube1 is required for both the initiation and maintenance of MLL-AF9–induced leukemogenesis in vivo. Molecular, genetic, proteomic and biochemical studies further demonstrate that the membrane-tethered SCUBE1 is essential for the initiation and maintenance of MLL-r leukemias by augmenting the proliferative and survival signaling axis mediated by Fms-like receptor tyrosine kinase 3 (FLT3)–Lck/Yes-related novel protein tyrosine kinase (LYN). In addition, we demonstrate that an anti-SCUBE1 monomethyl auristatin E (an anti-microtubule cytotoxin) antibody–drug conjugate (ADC) executes specific and enhanced anti-leukemic effects in SCUBE1-positive MLL-r AML cells. These results suggest that targeting the cell-surface SCUBE1 might be an efficient and promising strategy for treating MLL-r AML.
This study was accomplished by a team led by Dr. Ruey-Bing Yang (Academia Sinica). The first author, Binay K. Sahoo, is a Ph. D. student of Taiwan International Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica. The second and third authors, Yuh-Charn Lin and Cheng-Fen Tu, are Post-Doctoral Fellow in Dr. Ruey-Bing Yang’ Lab. in Institute of Biomedical Sciences, Academia Sinica.
The article entitled “Signal peptide-CUB-EGF-like repeat-containing protein 1-promoted FLT3 signaling is critical for the initiation and maintenance of MLL-rearranged acute leukemia”, can be read online at: https://haematologica.org/article/view/haematol.2022.281151