Postdoctoral Fellow University of Michigan Ann Arbor, Michigan, United States
Disclosure(s):
Francisco Gomez-Rivera, PhD: No financial relationships to disclose
Introduction/Rationale: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood cancer in children and adults, marked by the uncontrolled growth of immature T cells infiltrating the bone marrow, with frequent peripheral blood, mediastinal, and central nervous system involvement. Our lab found that Zinc Finger MIZ-containing 1 (ZMIZ1), a transcription cofactor in the PIAS-like family, drives NOTCH1-mutated and early precursor T-ALL. ZMIZ1 binds various transcription factors, influencing development and disease. We identified somatic mutations in the alanine-rich domain (ARD) of ZMIZ1 in T-ALL patients and found these mutations are mutually exclusive with germline ARD mutations seen in neurodevelopmental disorder (NEDDFSA). The ARD’s function is unknown.
Methods: We aim to uncover ARD’s role in T-ALL by studying these mutations. We cloned WT and mutant ZMIZ1 into retroviruses and transduced them into ZMIZ1-deficient 8946 T-ALL cells.
Results: T-ALL mutants showed increased ZMIZ1 protein levels compared to WT, while a NEDDFSA mutant showed decreased levels, with mRNA unchanged, indicating effects on protein stability. Deleting ARD (ΔARD) raised ZMIZ1 abundance 2.5-fold, suggesting ARD acts as a degron; cycloheximide treatment supported higher stability in ΔARD cells. Preliminary data link ARD mutations to faster cell growth versus WT. To further study ARD, we made GFP-ARD chimeras with T-ALL and NEDDFSA mutations, finding T-ALL mutants had higher expression than NEDDFSA ones. Proteasome inhibition increased GFP-ARD levels, indicating ARD-induced degradation is proteasome-dependent. Our data suggest adjacent ARD mutations can either drive T-ALL or neurodevelopmental disorders by affecting ZMIZ1 stability.
Conclusion: Understanding ARD regulation of ZMIZ1 may open therapies for ZMIZ1-dependent cancers, as these mutations also appear in brain, breast, B-cell, and myeloid cancers.
