title: Prognostic significance of expression levels of stem cell regulators MSI2 and NUMB in acute myeloid leukemia.
abstract: Deregulation of the hematopoietic stem cell (HSC) compartment represents a hallmark of acute myeloid leukemia (AML). Recently, in vivo screening for genes that are involved in the regulation of HSCs has led to the discovery of Musashi-2 (MSI2) as a key regulator of HSCs and as a suppressor of NUMB. In order to analyze the prognostic importance of MSI2 and NUMB expression in AML, MSI2 and NUMB transcript levels from 454 AML patients treated in multicenter trials AML SHG 0199 (ClinicalTrials Identifier NCT00209833) and 0295, and 38 healthy volunteers were analyzed by reverse transcriptase PCR in the context of other molecular markers (NPM1, FLT3, CEBPA, IDH1/IDH2, DNMT3A, NRAS, WT1, KIT, MN1, BAALC, ERG, and WT1). In AML, patients with high MSI2 expression were more likely to be FLT3-ITD positive (P < .001), NPM1 (P < .001), and DNMT3A (P = .003) mutated. Overall survival (OS) was shorter in AML patients with high MSI2 expression (hazard ratio, 1.48; 95 % confidence interval, 1.13-1.95, P = .005). However, relapse-free survival (RFS, P = .15) and complete remission (CR, P = .39) rates were not influenced by MSI2 expression. In multivariate analysis, MSI2 expression remained an independent prognostic factor for OS (P = .03). NUMB expression had no impact on survival (OS, P = .47; RFS, P = .59) and CR rate (P = .39). MSI2 but not NUMB is associated with shorter OS in AML patients and may indicate a more aggressive form of AML.
authors.affiliation: Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany. thol.felicitas@mh-hannover.de
authors.forename: Felicitas
authors.initials: F
authors.lastname: Thol
authors.forename: Claudia
authors.initials: C
authors.lastname: Winschel
authors.forename: Ann-Kathrin
authors.initials: AK
authors.lastname: Sonntag
authors.forename: Frederik
authors.initials: F
authors.lastname: Damm
authors.forename: Katharina
authors.initials: K
authors.lastname: Wagner
authors.forename: Anuhar
authors.initials: A
authors.lastname: Chaturvedi
authors.forename: Gudrun
authors.initials: G
authors.lastname: Göhring
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schlegelberger
authors.forename: Michael
authors.initials: M
authors.lastname: Lübbert
authors.forename: Walter
authors.initials: W
authors.lastname: Fiedler
authors.forename: Hartmut
authors.initials: H
authors.lastname: Kirchner
authors.forename: Jürgen
authors.initials: J
authors.lastname: Krauter
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
authors.forename: Michael
authors.initials: M
authors.lastname: Heuser
mesh_terms: D000293:Adolescent; D000328:Adult; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000378:metabolism* / Q000401:mortality; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis*; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D000090243:Nucleophosmin; D011379:Prognosis; D016601:RNA-Binding Proteins / Q000096:biosynthesis*; D015996:Survival Rate / Q000639:trends; D055815:Young Adult
chemical_list: C438151:MSI2 protein, human; D008565:Membrane Proteins; C000716967:NPM1 protein, human; D009419:Nerve Tissue Proteins; C113026:NUMB protein, human; D016601:RNA-Binding Proteins; D000090243:Nucleophosmin