The depletion of PHF6 decreases the drug sensitivity of T-cell acute lymphoblastic leukemia to prednisolone.

Mutation of PHF6 has been identified in Börjeson-Forssman-Lehmann syndrome and some types of subsets of childhood leukemia. However, the molecular function and the relationship of PHF6 mutation with glucocorticoid drug resistance during T-ALL treatment remains elusive. Here we report the influence of PHF6 expression on the drug response of T-ALL to prednisolone, and the underlying mechanism of this. Through sanger sequencing and western blotting assays, we identified two T-ALL cell lines with wild-type PHF6 expression, including SIL-ALL and CCRF-CEM, and two T-ALL cell lines without PHF6 expression, including TALL-1 and HPB-ALL, due to the nonsense and frameshift mutations in the coding region of PHF6. MTT assays showed that SIL-ALL and CCRF-CEM were much more sensitive to prednisolone. However, TALL-1 and HPB-ALL were much more resistance to prednisolone. Further knockout of PHF6 led to the resistant of both SIL-ALL and CCRF-CEM cells to prednisolone. On the contrary, the correction of the PHF6 point mutation in HPB-ALL cells with CRISPR-CAS9 method increased the sensibility of both cell lines to prednisolone. Then we found that PHF6 repress p21 expression through direct binding and recruiting RBPP4 to its promoter region. Finally, the co-treatment of p21 inhibitor increased the sensitivity of TALL-1 and HPB-ALL cells to prednisolone. Collectively, our findings not only enrich our understanding of the relationship between PHF6 mutation and drug resistance but also indicate a new therapeutic potential for those T-ALL patients containing the PHF6 mutation.