Abstract
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.
Keywords:
BMP pathway; T-ALL; homeobox; lymphopoiesis.
MeSH terms
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Bone Morphogenetic Proteins / antagonists & inhibitors
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Bone Morphogenetic Proteins / genetics*
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Cell Line, Tumor
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Child
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Eye Proteins / genetics
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Forkhead Transcription Factors / genetics
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GATA2 Transcription Factor / genetics
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GATA3 Transcription Factor / genetics
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Gene Expression Profiling*
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Gene Expression Regulation, Leukemic*
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Gene Regulatory Networks
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Humans
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Jurkat Cells
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Lymphoid Enhancer-Binding Factor 1 / genetics
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MSX1 Transcription Factor / genetics*
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Nerve Tissue Proteins / genetics
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Oligonucleotide Array Sequence Analysis
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Paired Box Transcription Factors / genetics
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Proto-Oncogene Proteins / genetics
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / genetics*
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T-Cell Acute Lymphocytic Leukemia Protein 1
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T-Lymphocytes / metabolism
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T-Lymphocytes / pathology
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Bone Morphogenetic Proteins
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CHRDL1 protein, human
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Eye Proteins
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FOXC1 protein, human
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Forkhead Transcription Factors
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GATA2 Transcription Factor
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GATA2 protein, human
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GATA3 Transcription Factor
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GATA3 protein, human
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LEF1 protein, human
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Lymphoid Enhancer-Binding Factor 1
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MSX1 Transcription Factor
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MSX1 protein, human
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Nerve Tissue Proteins
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Paired Box Transcription Factors
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Proto-Oncogene Proteins
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T-Cell Acute Lymphocytic Leukemia Protein 1
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homeobox protein PITX1
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TAL1 protein, human