Aberrant activity of NKL homeobox gene NKX3-2 in a T-ALL subset

T-cell acute lymphoblastic leukemia (T-ALL) is a hematopoietic malignancy originating from T-cell progenitors in which differentiation is blocked at early stages. Physiological expression of specific NKL homeobox genes obeys a hematopoietic NKL-code implicated in the process of lymphopoiesis while i...

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Bibliographic Details
Published in:PloS one 2018-05, Vol.13 (5), p.e0197194-e0197194
Main Authors: Nagel, Stefan, Meyer, Corinna, Kaufmann, Maren, Zaborski, Margarete, MacLeod, Roderick A F, Drexler, Hans G
Format: Article
Language:English
Subjects:
Aberration
Acute lymphoblastic leukemia
Acute lymphocytic leukemia
Biology and Life Sciences
Bone morphogenetic proteins
Cancer
Care and treatment
Cell culture
Cell differentiation
Cellular signal transduction
Chromosome 4
Deregulation
Development and progression
Differentiation (biology)
Fibroblasts
Foxg1 protein
GATA-3 protein
Gene expression
Gene silencing
Genes
Genetic aspects
Genomes
Growth factors
Health aspects
Hemopoiesis
Homeobox
Leukemia
Lymphatic leukemia
Lymphocytes T
Lymphoma
Lymphopoiesis
Malignancy
MAP kinase
Medicine and Health Sciences
Microorganisms
MicroRNAs
Nkx2.5 protein
Pathogenesis
Patients
Prostate
Research and Analysis Methods
Signal transduction
SIX gene family
Spleen
Tlx1 protein
Tlx3 protein
Transcription factors
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Summary:T-cell acute lymphoblastic leukemia (T-ALL) is a hematopoietic malignancy originating from T-cell progenitors in which differentiation is blocked at early stages. Physiological expression of specific NKL homeobox genes obeys a hematopoietic NKL-code implicated in the process of lymphopoiesis while in differentiated T-cells these genes are silenced. We propose that this developmental expression pattern underlies the observation that NKL homeobox genes are the most ubiquitous group of transcription factors deregulated in T-ALL, including TLX1, TLX3, NKX2-5 and NKX3-1. Here, we describe a novel member of the NKL homeobox gene subclass, NKX3-2 (BAPX1), which is aberrantly activated in 18% of pediatric T-ALL patients analyzed while being normally expressed in developing spleen. Identification of NKX3-2 expression in T-ALL cell line CCRF-CEM qualified these cells to model its deregulation and function in a leukemic context. Genomic and chromosomal analyses demonstrated normal configuration of the NKX3-2 locus at chromosome 4p15, thus excluding cytogenetic dysregulation. Comparative expression profiling analysis of NKX3-2 patient data revealed deregulated activity of BMP- and MAPK-signalling. These candidate pathways were experimentally confirmed to mediate aberrant NKX3-2 expression. We also show that homeobox gene SIX6, plus MIR17HG and GATA3 are downstream targets of NKX3-2 and plausibly contribute to the pathogenesis of this malignancy by suppressing T-cell differentiation. Finally, NKL homeobox gene NKX2-5 was activated by NKX3-2 in CCRF-CEM and by FOXG1 in PEER, representing mutually inhibitory activators of this translocated oncogene. Together, our findings reveal a novel oncogenic NKL homeobox gene subclass member which is aberrantly expressed in a large subset of T-ALL patients and participates in a deregulated gene network likely to arise in developing spleen.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0197194