title: Somatic deletions of genes regulating MSH2 protein stability cause DNA mismatch repair deficiency and drug resistance in human leukemia cells.
abstract: DNA mismatch repair enzymes (for example, MSH2) maintain genomic integrity, and their deficiency predisposes to several human cancers and to drug resistance. We found that leukemia cells from a substantial proportion of children (∼11%) with newly diagnosed acute lymphoblastic leukemia have low or undetectable MSH2 protein levels, despite abundant wild-type MSH2 mRNA. Leukemia cells with low levels of MSH2 contained partial or complete somatic deletions of one to four genes that regulate MSH2 degradation (FRAP1 (also known as MTOR), HERC1, PRKCZ and PIK3C2B); we also found these deletions in individuals with adult acute lymphoblastic leukemia (16%) and sporadic colorectal cancer (13.5%). Knockdown of these genes in human leukemia cells recapitulated the MSH2 protein deficiency by enhancing MSH2 degradation, leading to substantial reduction in DNA mismatch repair and increased resistance to thiopurines. These findings reveal a previously unrecognized mechanism whereby somatic deletions of genes regulating MSH2 degradation result in undetectable levels of MSH2 protein in leukemia cells, DNA mismatch repair deficiency and drug resistance.
authors.affiliation: Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Barthelemy
authors.initials: B
authors.lastname: Diouf
authors.forename: Qing
authors.initials: Q
authors.lastname: Cheng
authors.forename: Natalia F
authors.initials: NF
authors.lastname: Krynetskaia
authors.forename: Wenjian
authors.initials: W
authors.lastname: Yang
authors.forename: Meyling
authors.initials: M
authors.lastname: Cheok
authors.forename: Deqing
authors.initials: D
authors.lastname: Pei
authors.forename: Yiping
authors.initials: Y
authors.lastname: Fan
authors.forename: Cheng
authors.initials: C
authors.lastname: Cheng
authors.forename: Evgeny Y
authors.initials: EY
authors.lastname: Krynetskiy
authors.forename: Hui
authors.initials: H
authors.lastname: Geng
authors.forename: Siying
authors.initials: S
authors.lastname: Chen
authors.forename: William E
authors.initials: WE
authors.lastname: Thierfelder
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.forename: James R
authors.initials: JR
authors.lastname: Downing
authors.forename: Peggy
authors.initials: P
authors.lastname: Hsieh
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.forename: Mary V
authors.initials: MV
authors.lastname: Relling
authors.forename: William E
authors.initials: WE
authors.lastname: Evans
mesh_terms: D000328:Adult; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002648:Child; D058541:Class II Phosphatidylinositol 3-Kinases; D053843:DNA Mismatch Repair / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency; D006801:Humans; D051718:MutS Homolog 2 Protein / Q000235:genetics* / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism*; D016016:Proportional Hazards Models; D011493:Protein Kinase C / Q000172:deficiency; D058570:TOR Serine-Threonine Kinases / Q000172:deficiency; D013866:Thioguanine; D044767:Ubiquitin-Protein Ligases; D000099221:Protein Kinase C zeta
chemical_list: D058541:Class II Phosphatidylinositol 3-Kinases; D020662:Guanine Nucleotide Exchange Factors; D051718:MutS Homolog 2 Protein; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D058570:TOR Serine-Threonine Kinases; D013866:Thioguanine; D044767:Ubiquitin-Protein Ligases; D000099221:Protein Kinase C zeta; C102169:HERC1 protein, human; C546842:MTOR protein, human; C502616:PIK3C2B protein, human; C497172:MSH2 protein, human