title: HDM4 (HDMX) is widely expressed in adult pre-B acute lymphoblastic leukemia and is a potential therapeutic target.
abstract: Human homolog of murine double minute 2 (HDM2) and HDM4 (or HDMX) are negative regulators of p53. HDM4 has not been assessed in precursor B (pre-B) lymphoblastic leukemia (ALL). We examined bone marrow samples obtained at time of diagnosis from 55 adults with pre-B ALL. A tissue microarray composed of 2 cores per specimen was constructed and immunohistochemical techniques were used to assess HDM4, HDM2, p53, and p21. HDM4 was expressed in 39 of 49 (80%) cases. HDM2 was expressed in 14 of 54 (26%). All HDM2-positive cases were also positive for HDM4 (P<0.05). We confirmed expression of HDM4 and HDM4 variants by Western blotting and sequencing of reverse transcription-polymerase chain reaction products in a subset of ALL tumors. Results were correlated with the presence of the Philadelphia chromosome (Ph). p53 (P<0.05) and p21 (P<0.001) were expressed significantly more often in Ph+ pre-B ALL. HDM4 and HDM2 showed no correlation with Ph status. HDM4 expression in most cases of adult pre-B ALL suggests that HDM4 is a potential therapeutic target.
authors.affiliation: Department of Laboratory Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Han
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: McDonnell
authors.forename: Guillermina
authors.initials: G
authors.lastname: Lozano
authors.forename: L Jeffrey
authors.initials: LJ
authors.lastname: Medeiros
authors.forename: Lianchun
authors.initials: L
authors.lastname: Xiao
authors.forename: Gary
authors.initials: G
authors.lastname: Rosner
authors.forename: Martin
authors.initials: M
authors.lastname: Nguyen
authors.forename: Michael
authors.initials: M
authors.lastname: Fernandez
authors.forename: Yasmine A
authors.initials: YA
authors.lastname: Valentin-Vega
authors.forename: Juan
authors.initials: J
authors.lastname: Barboza
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Jones
authors.forename: Georgios Z
authors.initials: GZ
authors.lastname: Rassidakis
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Bueso-Ramos
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D001853:Bone Marrow / Q000737:chemistry / Q000473:pathology*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000032:analysis*; D010677:Philadelphia Chromosome; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D011379:Prognosis; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000032:analysis*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D013997:Time Factors; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2