Oncogenic deregulation of NKL homeobox gene MSX1 in mantle cell lymphoma.
NKL homeobox gene MSX1 is physiologically expressed during embryonic hematopoiesis. Here, we detected MSX1 overexpression in three examples of mantle cell lymphoma (MCL) and one of acute myeloid leukemia (AML) by screening 96 leukemia/lymphoma cell lines via microarray profiling. Moreover, in silico analysis identified significant overexpression of MSX1 in 3% each of patients with MCL and AML, confirming aberrant activity in subsets of both types of malignancies. Comparative expression profiling analysis and subsequent functional studies demonstrated overexpression of histone acetyltransferase PHF16 together with transcription factors FOXC1 and HLXB9 as activators of MSX1 transcription. Additionally, we identified regulation of cyclin D1/CCND1 by MSX1 and its repressive cofactor histone H1C. Fluorescence in situ hybridization in MCL cells showed that t(11;14)(q13;q32) results in detachment of CCND1 from its corresponding repressive MSX1 binding site. Taken together, we uncovered regulators and targets of homeobox gene MSX1 in leukemia/lymphoma cells, supporting the view of a recurrent genetic network that is reactivated in malignant transformation.
Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ - German Collection of Microorganisms and Cell Cultures , Braunschweig , Germany.
Stefan
S
Nagel
Stefan
S
Ehrentraut
Corinna
C
Meyer
Maren
M
Kaufmann
Hans G
HG
Drexler
Roderick A F
RA
MacLeod
D000107:Acetylation; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D015448:Leukemia, B-Cell / Q000235:genetics / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000378:metabolism; D051957:MSX1 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation
C112743:FOXC1 protein, human; D051858:Forkhead Transcription Factors; D006657:Histones; D018398:Homeodomain Proteins; C490003:MNX1 protein, human; D051957:MSX1 Transcription Factor; D014157:Transcription Factors
Cyclin D1; hematopoiesis; homeobox