Repressed BMP signaling reactivates NKL homeobox gene MSX1 in a T-ALL subset.
In T-cell acute lymphoblastic leukemia (T-ALL), several members of the NK-like (NKL) homeobox genes are aberrantly expressed. Here, we have analyzed the activity of NKL homeobox gene MSX1 using pediatric T-ALL in silico data, detecting overexpression in 11% of patients. Quantification of MSX1 transcripts in a panel of 24 T-ALL cell lines demonstrated overexpression in two examples. Comparative expression profiling indicated inhibition of the bone morphogenetic protein (BMP) signaling pathway, which was shown to inhibit MSX1 transcription. In the LOUCY cell line we identified conspicuous expression of CHRDL1 encoding a BMP inhibitor which mediated activation of MSX1. Promoter analyses demonstrated activation of CHRDL1 by oncogenic PITX1. Furthermore, knockdown and overexpression studies of hematopoietic transcription factors demonstrated that GATA2 and FOXC1 mediate activation and GATA3, LEF1, TAL1 and TOX repression of MSX1 transcription. Collectively, our findings suggest that MSX1 is physiologically restricted to lymphoid progenitors. The identification of deregulated BMP signaling may provide novel therapeutic options for the treatment of T-ALL.
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
D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D045744:Cell Line, Tumor; D002648:Child; D005136:Eye Proteins / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000235:genetics; D050989:GATA2 Transcription Factor / Q000235:genetics; D050990:GATA3 Transcription Factor / Q000235:genetics; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D053263:Gene Regulatory Networks; D006801:Humans; D019169:Jurkat Cells; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics; D051957:MSX1 Transcription Factor / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D051761:Paired Box Transcription Factors / Q000235:genetics; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology
D051792:Basic Helix-Loop-Helix Proteins; D019485:Bone Morphogenetic Proteins; D005136:Eye Proteins; D051858:Forkhead Transcription Factors; D050989:GATA2 Transcription Factor; D050990:GATA3 Transcription Factor; D051821:Lymphoid Enhancer-Binding Factor 1; D051957:MSX1 Transcription Factor; D009419:Nerve Tissue Proteins; D051761:Paired Box Transcription Factors; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; C486602:CHRDL1 protein, human; C112743:FOXC1 protein, human; C494711:GATA2 protein, human; C494749:GATA3 protein, human; C497573:LEF1 protein, human; C484083:MSX1 protein, human; C101485:homeobox protein PITX1; C067143:TAL1 protein, human
BMP pathway; T-ALL; homeobox; lymphopoiesis