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

Overview

Journal Haematologica

Specialty Hematology

Date 2011 Mar 23

PMID 21422114

Citations 13

Authors

Claudia Haferlach

Ulrike Bacher

Alexander Kohlmann

Sonja Schindela

Tamara Alpermann

Wolfgang Kern

Susanne Schnittger

Torsten Haferlach

Affiliations

Soon will be listed here.

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.

Design And 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.

Citing Articles

Plasma protein changes reflect colorectal cancer development and associated inflammation.

Urbiola-Salvador V, Jablonska A, Miroszewska D, Huang Q, Duzowska K, Drezek-Chyla K Front Oncol. 2023; 13:1158261.

PMID: 37228491 PMC: 10203952. DOI: 10.3389/fonc.2023.1158261.

Cyclin-dependent kinase inhibitors in malignant hematopoiesis.

Schirripa A, Sexl V, Kollmann K Front Oncol. 2022; 12:916682.

PMID: 36033505 PMC: 9403899. DOI: 10.3389/fonc.2022.916682.

The Role of MicroRNA in DNA Damage Response.

Li Y, Tong Y, Liu J, Lou J Front Genet. 2022; 13:850038.

PMID: 35591858 PMC: 9110863. DOI: 10.3389/fgene.2022.850038.

Identification of circRNA-lncRNA-miRNA-mRNA Competitive Endogenous RNA Network as Novel Prognostic Markers for Acute Myeloid Leukemia.

Cheng Y, Su Y, Wang S, Liu Y, Jin L, Wan Q Genes (Basel). 2020; 11(8).

PMID: 32751923 PMC: 7465400. DOI: 10.3390/genes11080868.

Exosomes released from M2 macrophages transfer miR-221-3p contributed to EOC progression through targeting CDKN1B.

Li X, Tang M Cancer Med. 2020; 9(16):5976-5988.

PMID: 32590883 PMC: 7433826. DOI: 10.1002/cam4.3252.

References

Schnittger S, Dicker F, Kern W, Wendland N, Sundermann J, Alpermann T . RUNX1 mutations are frequent in de novo AML with noncomplex karyotype and confer an unfavorable prognosis. Blood. 2010; 117(8):2348-57. DOI: 10.1182/blood-2009-11-255976. View

Silva F, Morolli B, Storlazzi C, Zagaria A, Impera L, Klein B . ETV6 mutations and loss in AML-M0. Leukemia. 2008; 22(8):1639-43. DOI: 10.1038/leu.2008.34. View

Schnittger S, Kinkelin U, Schoch C, Heinecke A, Haase D, Haferlach T . Screening for MLL tandem duplication in 387 unselected patients with AML identify a prognostically unfavorable subset of AML. Leukemia. 2000; 14(5):796-804. DOI: 10.1038/sj.leu.2401773. View

Sato Y, Suto Y, Pietenpol J, Golub T, Gilliland D, Davis E . TEL and KIP1 define the smallest region of deletions on 12p13 in hematopoietic malignancies. Blood. 1995; 86(4):1525-33. View

Schnittger S, Kern W, Tschulik C, Weiss T, Dicker F, Falini B . Minimal residual disease levels assessed by NPM1 mutation-specific RQ-PCR provide important prognostic information in AML. Blood. 2009; 114(11):2220-31. DOI: 10.1182/blood-2009-03-213389. View

Bacher U, Haferlach T, Schoch C, Kern W, Schnittger S . Implications of NRAS mutations in AML: a study of 2502 patients. Blood. 2006; 107(10):3847-53. DOI: 10.1182/blood-2005-08-3522. View

Belletti B, Nicoloso M, Schiappacassi M, Chimienti E, Berton S, Lovat F . p27(kip1) functional regulation in human cancer: a potential target for therapeutic designs. Curr Med Chem. 2005; 12(14):1589-605. DOI: 10.2174/0929867054367149. View

Heuser M, Beutel G, Krauter J, Dohner K, von Neuhoff N, Schlegelberger B . High meningioma 1 (MN1) expression as a predictor for poor outcome in acute myeloid leukemia with normal cytogenetics. Blood. 2006; 108(12):3898-905. DOI: 10.1182/blood-2006-04-014845. View

Gupta M, Raghavan M, Gale R, Chelala C, Allen C, Molloy G . Novel regions of acquired uniparental disomy discovered in acute myeloid leukemia. Genes Chromosomes Cancer. 2008; 47(9):729-39. DOI: 10.1002/gcc.20573. View

10.

See W, Miller J, Squatrito M, Holland E, Resh M, Koff A . Defective DNA double-strand break repair underlies enhanced tumorigenesis and chromosomal instability in p27-deficient mice with growth factor-induced oligodendrogliomas. Oncogene. 2010; 29(12):1720-31. PMC: 2845739. DOI: 10.1038/onc.2009.465. View

11.

Schoch C, Schnittger S, Bursch S, Gerstner D, Hochhaus A, Berger U . Comparison of chromosome banding analysis, interphase- and hypermetaphase-FISH, qualitative and quantitative PCR for diagnosis and for follow-up in chronic myeloid leukemia: a study on 350 cases. Leukemia. 2002; 16(1):53-9. DOI: 10.1038/sj.leu.2402329. View

12.

Baldus C, Thiede C, Soucek S, Bloomfield C, Thiel E, Ehninger G . BAALC expression and FLT3 internal tandem duplication mutations in acute myeloid leukemia patients with normal cytogenetics: prognostic implications. J Clin Oncol. 2006; 24(5):790-7. DOI: 10.1200/JCO.2005.01.6253. View

13.

Schnittger S, Haferlach C, Ulke M, Alpermann T, Kern W, Haferlach T . IDH1 mutations are detected in 6.6% of 1414 AML patients and are associated with intermediate risk karyotype and unfavorable prognosis in adults younger than 60 years and unmutated NPM1 status. Blood. 2010; 116(25):5486-96. DOI: 10.1182/blood-2010-02-267955. View

14.

Akagi T, Ogawa S, Dugas M, Kawamata N, Yamamoto G, Nannya Y . Frequent genomic abnormalities in acute myeloid leukemia/myelodysplastic syndrome with normal karyotype. Haematologica. 2009; 94(2):213-23. PMC: 2635399. DOI: 10.3324/haematol.13024. View

15.

Toyoshima H, Hunter T . p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell. 1994; 78(1):67-74. DOI: 10.1016/0092-8674(94)90573-8. View

16.

Stegmaier K, Takeuchi S, Golub T, Bohlander S, Bartram C, Koeffler H . Mutational analysis of the candidate tumor suppressor genes TEL and KIP1 in childhood acute lymphoblastic leukemia. Cancer Res. 1996; 56(6):1413-7. View

17.

Bacher U, Haferlach C, Kern W, Haferlach T, Schnittger S . Prognostic relevance of FLT3-TKD mutations in AML: the combination matters--an analysis of 3082 patients. Blood. 2007; 111(5):2527-37. DOI: 10.1182/blood-2007-05-091215. View

18.

Kohlmann A, Kipps T, Rassenti L, Downing J, Shurtleff S, Mills K . An international standardization programme towards the application of gene expression profiling in routine leukaemia diagnostics: the Microarray Innovations in LEukemia study prephase. Br J Haematol. 2008; 142(5):802-7. PMC: 2654477. DOI: 10.1111/j.1365-2141.2008.07261.x. View

19.

Snaddon J, Smith M, Neat M, Cambal-Parrales M, Dixon-McIver A, Arch R . Mutations of CEBPA in acute myeloid leukemia FAB types M1 and M2. Genes Chromosomes Cancer. 2003; 37(1):72-8. DOI: 10.1002/gcc.10185. View

20.

Schoch C, Kohlmann A, Dugas M, Kern W, Hiddemann W, Schnittger S . Genomic gains and losses influence expression levels of genes located within the affected regions: a study on acute myeloid leukemias with trisomy 8, 11, or 13, monosomy 7, or deletion 5q. Leukemia. 2005; 19(7):1224-8. DOI: 10.1038/sj.leu.2403810. View