title: High Expression of Human Homologue of Murine Double Minute 4 and the Short Splicing Variant, HDM4-S, in Bone Marrow in Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome.
abstract: The human homologue of murine double minute 2 (HDM2) and HDM4 negatively regulate p53. HDM4 has not been assessed in acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). We examined the expression of HDM4 and the short splicing variant, HDM4-S, in bone marrow samples obtained from 85 and 23 patients with AML and MDS, respectively, and 18 negative tumor staging bone marrow samples (used as the control). Immunohistochemical staining showed that HDM4 was overexpressed in 78 AML cases (92%) and 12 MDS cases (52%) compared with 1 stressed bone marrow sample (6%). Quantitative reverse transcriptase-polymerase chain reaction analysis of 8 AML and 11 low-grade (LG)-MDS cases confirmed that HDM4 and HDM4-S mRNA expression were also elevated in all AML cases. HDM4 and HDM4-S mRNA expression was elevated in 3 (27%) and 10 (91%) LG-MDS cases, respectively. HDM4 and HDM4-S mRNA levels were higher in those with AML than in those with LG-MDS. In leukemia cell lines, HEL and U937 predominantly expressed HDM4-S. In contrast, NALM6 expressed HDM4 and HDM4-S. Downregulation of HDM4 expression by treatment with small interfering RNA in NALM6 and HEL cells induced p21 expression but not increased apoptotic activity. Our results indicate that HDM4 is a potential therapeutic target in patients with AML or MDS.
authors.affiliation: Department of Laboratory Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Xin
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: L Jeffrey
authors.initials: LJ
authors.lastname: Medeiros
authors.affiliation: Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Yu Helen
authors.initials: YH
authors.lastname: Zhang
authors.affiliation: Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: M James
authors.initials: MJ
authors.lastname: You
authors.affiliation: Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.affiliation: Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
authors.affiliation: Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX. Electronic address: cbuesora@mdanderson.org.
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Bueso-Ramos
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing; D001853:Bone Marrow / Q000473:pathology; D001854:Bone Marrow Cells / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D005260:Female; D015870:Gene Expression; D015973:Gene Expression Regulation, Leukemic; D011905:Genes, ras; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051941:fms-Like Tyrosine Kinase 3
keywords: Acute myeloid leukemia; HDM4; HDM4-S; Myelodysplastic syndrome; p53