A critical role for phosphatase haplodeficiency in the selective suppression of deletion 5q MDS by lenalidomide.
Lenalidomide is the first karyotype-selective therapeutic approved for the treatment of myelodysplastic syndromes (MDS) owing to high rates of erythroid and cytogenetic response in patients with chromosome 5q deletion [del(5q)]. Although haploinsufficiency for the RPS14 gene and others encoded within the common deleted region (CDR) have been implicated in the pathogenesis of the del(5q) phenotype, the molecular basis of the karyotype specificity of lenalidomide remains unexplained. We focused our analysis on possible haplodeficient enzymatic targets encoded within the CDR that play key roles in cell-cycle regulation. We show that the dual specificity phosphatases, Cdc25C and PP2Acalpha, which are coregulators of the G(2)-M checkpoint, are inhibited by lenalidomide. Gene expression was lower in MDS and acute myeloid leukemia (AML) specimens with del(5q) compared with those with alternate karyotypes. Lenalidomide inhibited phosphatase activity either directly (Cdc25C) or indirectly (PP2A) with corresponding retention of inhibitory phospho-tyrosine residues. Treatment of del(5q) AML cells with lenalidomide induced G(2) arrest and apoptosis, whereas there was no effect in nondel(5q) AML cells. Small interfering RNA (shRNA) suppression of Cdc25C and PP2Acalpha gene expression recapitulated del(5q) susceptibility to lenalidomide with induction of G(2) arrest and apoptosis in both U937 and primary nondel(5q) MDS cells. These data establish a role for allelic haplodeficiency of the lenalidomide inhibitable Cdc25C and PP2Acalpha phosphatases in the selective drug sensitivity of del(5q) MDS.
Wei
Sheng
S
Immunology Program and Malignant Hematology Program, Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Chen
Xianghong
X
Rocha
Kathy
K
Epling-Burnette
P K
PK
Djeu
Julie Y
JY
Liu
Qing
Q
Byrd
John
J
Sokol
Lubomir
L
Lawrence
Nick
N
Pireddu
Roberta
R
Dewald
Gordon
G
Williams
Ann
A
Maciejewski
Jaroslaw
J
List
Alan
A
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D000077269:Lenalidomide; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology; D020298:U937 Cells; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors* / Q000235:genetics
D000970:Antineoplastic Agents; D013792:Thalidomide; C517189:PPP2CA protein, human; D054648:Protein Phosphatase 2; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases; D000077269:Lenalidomide