Abstract
Dynamin-2 (DNM2) is a GTPase essential for intracellular vesicle formation and trafficking, cytokinesis and receptor endocytosis. Mutations in DNM2 are common in early T-cell precursor acute lymphoblastic leukemia. However, DNM2 expression in other types of ALL are not reported. We studied DNM2 mRNA level in adults with B- and T-cell ALL. We found DNM2 is more highly expressed compared with normals in both forms of ALL. High DNM2 expression is associated with some clinical and laboratory features, inferior outcomes and with leukaemia cell proliferation. We also found Ikaros directly binds the DNM2 promoter and suppresses DNM2 expression. Consequently IKZF1 deletion is associated with high DNM2 expression. Conversely, casein kinase-2 (CK2)-inhibitor increases Ikaros function thereby inhibiting DNM2 expression. Inhibiting DNM2 suppresses proliferation of leukemia cells and synergizes with CK2 inhibition. Our data indicate high DNM2 expression is associated with Ikaros dysregulation and may be important in the development of B-ALL.
Highlights
IZKFI encodes the DNA-binding zinc finger protein Ikaros essential for normal hematopoiesis and immune development[7,8,9,10,11]
In B-cell ALL, high DNM2 mRNA levels were associated with a WBC ≥ 30 × 10E + 9/L compared to low DNM2 expression
We found IKZF1 mRNA levels were inversely-correlated with high DNM2 expression in both cohorts (Supplemental Figures 4 and 5)
Summary
IZKFI encodes the DNA-binding zinc finger protein Ikaros essential for normal hematopoiesis and immune development[7,8,9,10,11]. Ikaros is a tumor suppressor gene in acute B- and T-cell ALL11-14. We reported the Ikaros global binding profiling in ALL cells. We found Ikaros regulates expression of its targets through chromatin remodeling in ALL15-18. We found CK2-inhibitors increase tumor suppressor activity of Ikaros and act as a functional activator of Ikaros[15,16,17]. Our ChIP-seq data indicate Ikaros binding peaks in the promoter region of DNM2. It is unclear how Ikaros regulates DNM2 expression. Our data suggest high expression of DNM2 with consequent Ikaros dysfunction is associated with development of B-cell ALL
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