title: Expression of CDKN1C in the bone marrow of patients with myelodysplastic syndrome and secondary acute myeloid leukemia is associated with poor survival after conventional chemotherapy.
abstract: We tested the hypothesis that proliferative activity of hematopoietic stem cells has impact on survival in newly diagnosed patients with myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (AML). RNA expression profiles of CD34(+) cells were analyzed in 125 MDS patients and compared to healthy controls. Prognostic impact on overall survival (OS) of mRNA proliferation signatures established for solid tumor cells was analyzed retrospectively. For validation on the protein level, immunofluorescence and immunohistochemistry analyses in bone marrow (BM) biopsies were performed, and an independent cohort of 223 MDS and secondary AML patients was investigated. Lower proliferative activity correlated with the expression of cyclin-dependent kinase inhibitor 1C (CDKN1C) and with shorter OS (p < 0.001). In multivariable analysis, higher CDKN1C expression was associated with worse OS (p = 0.02). On the BM level, a total of 84 (38%) patients showed CDKN1C protein expression before start of treatment. Patient, disease and treatment characteristics did not differ between CDKN1C-positive and -negative patients. Positive CDKN1C BM status was associated with shorter OS in multivariable analysis (HR 1.54, p = 0.04). There was an interaction between CDKN1C BM status and subsequent treatment with negative impact on OS being most pronounced in patients receiving conventional cytotoxic chemotherapy (n = 83, 2-year OS 30% versus 58%, p = 0.002). In conclusion, low-proliferative phenotype and CDKN1C expression were associated with shorter OS. CDKN1C protein expression in the BM of newly diagnosed, treatment-naïve MDS and secondary AML patients was identified as a prognostic factor for poor survival in patients treated with antiproliferative chemotherapy.
authors.affiliation: Department of Internal Medicine V, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Radujkovic
authors.affiliation: Department of Internal Medicine V, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Dietrich
authors.affiliation: Institute of Pathology, University of Ulm, Ulm, Germany.|Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Mindaugas
authors.initials: M
authors.lastname: Andrulis
authors.affiliation: Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Benner
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.|Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Longerich
authors.affiliation: Bloodwise Molecular Hematology Unit, NDCLS, University of Oxford, Oxford, United Kingdom.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pellagatti
authors.affiliation: Department of Internal Medicine V, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Kriti
authors.initials: K
authors.lastname: Nanda
authors.affiliation: National Center for Tumor Diseases and Institute of Immunology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Giese
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Germing
authors.affiliation: Institute of Pathology, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Baldus
authors.affiliation: Bloodwise Molecular Hematology Unit, NDCLS, University of Oxford, Oxford, United Kingdom.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Boultwood
authors.affiliation: Department of Internal Medicine V, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Ho
authors.affiliation: Department of Internal Medicine V, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Dreger
authors.affiliation: Department of Internal Medicine V, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Luft
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018952:Antigens, CD34 / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D015415:Biomarkers; D001853:Bone Marrow / Q000378:metabolism* / Q000473:pathology; D001854:Bone Marrow Cells / Q000378:metabolism; D049109:Cell Proliferation; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D016609:Neoplasms, Second Primary / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality*; D011379:Prognosis; D015398:Signal Transduction; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D018952:Antigens, CD34; D015415:Biomarkers; C493964:CDKN1C protein, human; D050761:Cyclin-Dependent Kinase Inhibitor p57
keywords: AML; CDKN1C; MDS; chemotherapy; p57; survival