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Center point:
Center point:The high expression of PRMT1 maintains the survival and growth of MLL-r ALL cells by regulating FLT3 methylation at R972/973
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PRMT1 inhibition can enhance the clearance of MLL-r ALL by tyrosine kinase inhibitor treatment
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Recurrence is still the main reason for treatment failure of acute lymphoblastic leukemia (ALL) with MLL rearrangement (MLL-r).
The main cause of recurrence is the persistence of resistant clones after conventional chemotherapy or targeted therapy
.
Therefore, it is important to clarify the potential maintenance mechanism of MLL-r ALL for the development of new effective treatments
The main cause of recurrence is the persistence of drug-resistant clones after conventional chemotherapy or targeted therapy
PRMT1, which can be deposited on histone/non-histone proteins to form an asymmetric dimethylarginine tag, is reported to be overexpressed in various cancers
.
PRMT1 is highly expressed in MLL-r ALL cells
PRMT1 is highly expressed in MLL-r ALL cellsIn this study, the researchers found that the expression level of PRMT1 in MLL-r ALL cells increased , and proved that PRMT1 inhibition can significantly inhibit the growth and survival of leukemia cells
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PRMT1 inhibition can significantly inhibit the growth and survival of leukemia cells
Inhibition of PRMT1 can inhibit the growth and survival of leukemia cells
Inhibition of PRMT1 can inhibit the growth and survival of leukemia cellsMechanistically, PRMT1 methylates the Fms-like receptor tyrosine kinase 3 (FLT3) at residues 972 and 973 (R972/973) of arginine (R) in a FLT3 methylation-dependent manner.
MLL-r ALL cells play a carcinogenic effect
.
Both biochemical and computational analysis indicate that R972/973 methylation can promote the recruitment of adaptor protein to FLT3 in a phosphotyrosine (Y) residue 969 (Y969) dependent or independent manner
PRMT1 methylates the Fms-like receptor tyrosine kinase 3 (FLT3) at residues 972 and 973 (R972/973) of arginine (R) in a FLT3 methylation-dependent manner in MLL-r ALL Carcinogenic effect in cells
Survival rate of transplanted tumor mice transplanted with different FLT3-deficient cells
Survival rate of transplanted tumor mice transplanted with different FLT3-deficient cellsCompared with FLT3 transduced cells deficient in Y969 phosphorylation, cells expressing FLT3 deficient in R972/973 methylation showed stronger apoptosis and growth inhibition
.
In addition, the researchers also found that the ability of the type I PRMT inhibitor MS023 to inhibit the viability of leukemia cells paralleled the baseline FLT3 R972/973 methylation level
Compared with FLT3 transduced cells deficient in Y969 phosphorylation, cells expressing FLT3 deficient in R972/973 methylation showed stronger apoptosis and growth inhibition
Survival rate of transplanted tumor mice treated with different regimens
Survival rate of transplanted tumor mice treated with different regimensFinally, in patient-derived mouse xenograft tumors, compared with the FLT3 tyrosine kinase inhibitor PKC412 treatment alone, PKC412 combined with MS023 treatment can enhance the clearance of MLL-r ALL cells
Compared with treatment with FLT3 tyrosine kinase inhibitor PKC412 alone, PKC412 combined with MS023 treatment can enhance the clearance of MLL-r ALL cells
Summary diagram
Summary diagramIn summary, the results of this study indicate that the elimination of FLT3 arginine methylation by inhibiting PRMT1 represents a promising therapeutic strategy targeting MLL-r ALL cells
Elimination of FLT3 arginine methylation by inhibiting PRMT1 represents a promising therapeutic strategy targeting MLL-r ALL cells
Original source:
Original source:Yinghui Zhu, et al.
Targeting PRMT1-mediated FLT3 methylation disrupts maintenance of MLL-rearranged acute lymphoblastic leukemia in this message
