title: CDKN1B, encoding the cyclin-dependent kinase inhibitor 1B (p27), is located in the minimally deleted region of 12p abnormalities in myeloid malignancies and its low expression is a favorable prognostic marker in acute myeloid leukemia.
abstract: BACKGROUND
  Alterations of the short arm of chromosome 12 (12p) occur in various hematologic malignancies and ETV6 and CDKN1B, which are located on 12p, have been implicated as leukemogenic genes of interest.
  
  
  METHODS
  We selected seven patients with myeloid malignancies and small 12p deletions detected by fluorescence in situ hybridization encompassing only the region centromeric of ETV6 and further evaluated them by single nucleotide polymorphism microarrays.
  
  
  RESULTS
  The minimally deleted region contained only nine genes. These genes were subsequently analyzed by microarray expression profiling in an independent cohort of 781 patients, most, but not all, of whom had different hematologic malignancies CREBL2, MANSC1, and CDKN1B were expressed in more than 25% of cases, while the other six genes were expressed in only a minority of cases. As CDKN1B is a cell cycle regulator and functions as a tumor suppressor gene, this gene was selected for further expression studies in 286 patients with acute myeloid leukemia. When comparing patients with low CDKN1B expression (expression level<1,160; 1st quartile) with those with intermediate or high expression (2nd-4th quartiles), certain mutations were observed more frequently in the former: RUNX1-RUNX1T1 (11/83, 13.3% versus 5/203; 2.5%; P=0.001), PML-RARA rearrangements (11/83, 13.3% versus 4/203, 2.0%; P<0.001), 11q23/MLL rearrangements (6/83, 7.2% versus 4/203, 2.0%; P=0.038), and FLT3-TKD mutations (7/63, 11.1% versus 6/167, 3.6%; P=0.047). The median overall survival of patients with low CDKN1B expression was longer than that of patients with intermediate/high expression (not reached versus 14.9 months; P=0.005). Likewise, patients with low CDKN1B expression had a longer event-free survival than those with intermediate/high expression (31.0 versus 9.7 months; P=0.013).
  
  
  CONCLUSIONS
  CDKN1B is an interesting candidate gene as a potential biomarker for prognostication in acute myeloid leukemia.
authors.affiliation: MLL, Munich Leukemia Laboratory, Max-Lebsche-Platz 31, 81377 Munich, Germany. claudia.haferlach@mll.com
authors.forename: Claudia
authors.initials: C
authors.lastname: Haferlach
authors.forename: Ulrike
authors.initials: U
authors.lastname: Bacher
authors.forename: Alexander
authors.initials: A
authors.lastname: Kohlmann
authors.forename: Sonja
authors.initials: S
authors.lastname: Schindela
authors.forename: Tamara
authors.initials: T
authors.lastname: Alpermann
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kern
authors.forename: Susanne
authors.initials: S
authors.lastname: Schnittger
authors.forename: Torsten
authors.initials: T
authors.lastname: Haferlach
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D002872:Chromosome Deletion; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011379:Prognosis; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D014408:Biomarkers, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger; D012097:Repressor Proteins; D000097764:ETS Translocation Variant 6 Protein