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What Factors Contribute to Functional Loss of SETD2 in CML?

By: Julia Fiederlein
Posted: Friday, October 16, 2020

According to Simona Soverini, PhD, of the University of Bologna, Italy, and colleagues, Aurora kinase A and mouse double minute 2 (MDM2) seem to be involved in the functional loss of the SET domain containing 2 (SETD2) tumor suppressor gene in advanced-phase chronic myeloid leukemia (CML). The results of this study, which were presented during the virtual edition of the 2020 Society of Hematologic Oncology (SOHO) Annual Meeting (Abstract CML-206), suggested this inactivation may be associated with increased DNA damage and impaired homologous recombination repair.

SETD2 is a tumor suppressor encoding a histone methyltransferase that trimethylates the histone H3 at lysine 36 (H3K36Me3),” the investigators commented, “and it is involved in the transcriptional regulation and repair of DNA damage.”

Reduced or null SETD2 and H3K36Me3 were observed in most patients with advanced-phase CML (88%). An accumulation of hyperubiquitinated SETD2 bound to MDM2 was observed after proteasome inhibition. Moreover, the pharmacologic inhibition of MDM2 by SP-141 and siRNA-mediated silencing suggested MDM2 may be involved in SETD2 loss. Aurora Kinase A was found to be overexpressed in CML; the results also indicated that it co-immunoprecipitates with SETD2. The pharmacologic inhibition and knockdown of Aurora A seemed to rescue SETD2 and H3K36Me3 expression.

Cells with low or silenced SETD2 expression appeared to have significantly higher levels of histone H2AX phosphorylation. Additionally, these cells seemed to be unable to induce homologous recombination repair after DNA damage. After treatment with first- and second-generation proteasome inhibitors, the mononuclear cell fraction's clonogenic potential fraction from blast crisis seemed to be reduced. Compared with patients who have chronic-phase CML and patients who have CML in blast crisis and intermediate SETD2 levels and activity, specific inhibition of MDM2 may induce more significant effects in patients with CML in blast crisis who have low SETD2 levels and activity.

Disclosure: No information regarding conflicts of interest was provided.



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