Open AccessBortezomib suppresses self‐renewal and leukemogenesis of leukemia stem cell by NF‐ĸB‐dependent inhibition of CDK6 in MLL‐rearranged myeloid leukemia
Author(s) -
Zhou Bin,
Qin Yaqian,
Zhou Jingying,
Ruan Jichen,
Xiong Fang,
Dong Jinglai,
Huang Xingzhou,
Yu Zhijie,
Gao Shenmeng
Publication year - 2021
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.16377
Subject(s) - cyclin dependent kinase 6 , cancer research , myeloid leukemia , leukemia , biology , stem cell , progenitor cell , medicine , cell cycle , immunology , cell , cyclin dependent kinase , microbiology and biotechnology , genetics
Acute myeloid leukaemia (AML) with chromosomal rearrangements involving the H3K4 methyltransferase mixed‐lineage leukaemia (MLL) is an aggressive subtype with low overall survival. Bortezomib (Bort) is first applied in multiple myeloma. However, whether bort possesses anti‐self‐renewal and leukemogenesis of leukaemia stem cell (LSC) in AML with MLL rearrangements is still unclear. Here, we found that bort suppressed cell proliferation and decreased colony formation in human and murine leukaemic blasts. Besides, bort reduced the frequency and function of LSC, inhibited the progression, and extended the overall survival in MLL‐AF9 (MF9) ‐transformed leukaemic mice. Furthermore, bort decreased the percentage of human LSC (CD34 + CD38 ‐ ) cells and extended the overall survival in AML blasts‐xenografted NOD/SCID‐IL2Rγ (NSG) mice. Mechanistically, cyclin dependent kinase 6 ( CDK6 ) was identified as a bort target by RNA sequencing. Bort reduced the expressions of CDK6 by inhibiting NF ĸB recruitment to the promoter of CDK6 , leading to the abolishment of NF ĸB DNA‐binding activity for CDK6 promoter. Overexpression of CDK6 partially rescued bort‐induced anti‐leukemogenesis. Most importantly, bort had little side‐effect against the normal haematological stem and progenitor cell (HSPC) and did not affect CDK6 expression in normal HSPC. In conclusion, our results suggest that bort selectively targets LSC in MLL rearrangements. Bort might be a prospective drug for AML patients bearing MLL rearrangements.