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HOX11, a homeobox-containing T-cell oncogene on human chromosome 10q24.

ABSTRACT: A common chromosomal abnormality in childhood T-cell acute leukemia is a translocation, t(10;14) (q24;q11), that together with the variant t(7;10)(q35;q24) is present in up to 7% of this tumor type. The gene adjacent to the 10q24 region is transcriptionally activated after translocation to either TCRD (14q11) or TCRB (7q35). It encodes a homeobox gene closely related to the developmentally regulated homeotic genes of flies and mammals. The coding capacity of this activated gene, designated HOX11, is undisturbed in a T-cell line carrying the translocation t(7;10)(q35;q24). Therefore, the HOX11 homeobox gene seems to be involved in T-cell tumorigenesis.

SUBMITTER: Kennedy MA

PROVIDER: S-EPMC52618 | biostudies-other | 1991 Oct

REPOSITORIES: biostudies-other

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HOX11, a homeobox-containing T-cell oncogene on human chromosome 10q24.

Kennedy M A MA Gonzalez-Sarmiento R R Kees U R UR Lampert F F Dear N N Boehm T T Rabbitts T H TH

Proceedings of the National Academy of Sciences of the United States of America 19911001 20

A common chromosomal abnormality in childhood T-cell acute leukemia is a translocation, t(10;14) (q24;q11), that together with the variant t(7;10)(q35;q24) is present in up to 7% of this tumor type. The gene adjacent to the 10q24 region is transcriptionally activated after translocation to either TCRD (14q11) or TCRB (7q35). It encodes a homeobox gene closely related to the developmentally regulated homeotic genes of flies and mammals. The coding capacity of this activated gene, designated HOX11 ...[more]

PMID: 1681546

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G1/S transcriptional networks modulated by the HOX11/TLX1 oncogene of T-cell acute lymphoblastic leukemia.

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A yeast artificial chromosome containing the mouse homeobox cluster Hox-2.

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PBX2 and PBX3, new homeobox genes with extensive homology to the human proto-oncogene PBX1.

Project description:Two new homeobox genes, PBX2 and PBX3, were isolated on the basis of their extensive homology to PBX1, a novel human homeobox gene involved in t(1;19) translocation in acute pre-B-cell leukemias. The predicted Pbx2 and Pbx3 proteins are 92 and 94% identical to Pbx1 over a large region of 266 amino acids within and flanking their homeodomains, but all three proteins diverge significantly near their amino and carboxy termini. Chromosome in situ hybridizations demonstrated that the PBX genes are not clustered but map to separate chromosomal loci: PBX1, 1q23; PBX2, 3q22-23; PBX3, 9q33-34. Expression of PBX2 or PBX3 was not restricted to particular states of differentiation or development, as mRNA transcripts of these genes were detected in most fetal and adult tissues and all cell lines, unlike PBX1, which is not expressed in lymphoid cell lines. Similar to PBX1 RNA, PBX3 RNA is alternatively spliced to yield two translation products with different carboxy termini, a feature not observed for PBX2. Their extensive sequence similarity and widespread expression suggest a generalized, overlapping role for Pbx proteins in most cell types. Differences in their amino and carboxy termini may modulate their activities, mediated in part by differential splicing and, for PBX1, protein fusion following t(1;19) chromosomal translocation.

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Dpbx, a new homeobox gene closely related to the human proto-oncogene pbx1 molecular structure and developmental expression.

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The HOX11 gene encodes a DNA-binding nuclear transcription factor belonging to a distinct family of homeobox genes.

Project description:A translocation involving human chromosome 10, band q24, in a subset of T-cell acute leukemias disrupts a region surrounding the putative oncogene HOX11, which encodes a protein with a homeodomain. The HOX11 protein binds to a specific DNA sequence, it localizes to the cell nucleus, and it transactivates transcription of a reporter gene linked to a cis-regulatory element, suggesting that HOX11 functions in vivo as a positive transcription activator. PCR analysis shows that the HOX11 homeodomain is a member of a distinct class of homeodomains, representatives of which occur in murine and Drosophila genomes. These all contain a threonine residue in place of the more common isoleucine or valine in helix 3 of the homeodomain. HOX11 therefore appears to belong to a family of DNA-binding transactivators of transcription.

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Project description:The purpose of this research is to develop a method to screen a large number of potential driver mutations of acute myeloid leukemia (AML) using a retroviral cDNA library and murine bone marrow transduction-transplantation system. As a proof-of-concept, murine bone marrow (BM) cells were transduced with a retroviral cDNA library encoding well-characterized oncogenes and homeobox genes, and the virus-transduced cells were transplanted into lethally irradiated mice. The proto-oncogenes responsible for leukemia initiation were identified by PCR amplification of cDNA inserts from genomic DNA isolated from leukemic cells. In an initial screen of ten leukemic mice, the MYC proto-oncogene was detected in all the leukemic mice. Of ten leukemic mice, 3 (30%) had MYC as the only transgene, and seven mice (70%) had additional proto-oncogene inserts. We repeated the same experiment after removing MYC-related genes from the library to characterize additional leukemia-inducing gene combinations. Our second screen using the MYC-deleted proto-oncogene library confirmed MEIS1and the HOX family as cooperating oncogenes in leukemia pathogenesis. The model system we introduced in this study will be valuable in functionally screening novel combinations of genes for leukemogenic potential in vivo, and the system will help in the discovery of new targets for leukemia therapy.

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Transcriptional regulation of the human ALDH1A1 promoter by the oncogenic homeoprotein TLX1/HOX11

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The tcl-3 proto-oncogene altered by chromosomal translocation in T-cell leukemia codes for a homeobox protein.

Project description:The t(10;14)(q24;q11) chromosomal translocation found in malignant cells of 5-10% of patients with T-cell acute lymphoblastic leukemia (T-ALL) involves the T-cell receptor delta chain gene on chromosome 14 and a breakpoint cluster region on chromosome 10. The candidate proto-oncogene tcl-3, thought to be involved in the pathogenesis of t(10;14) T-ALL, was cloned and found to be elevated in expression in leukemic cells harboring the t(10;14) translocation. Sequence analysis revealed that tcl-3 is a new homeobox-containing gene. Comparison of the tcl-3 cDNA and its 5' genomic sequences with DNA sequences from the t(10;14) translocation breakpoints showed that this gene is structurally altered in four patients with t(10;14)(q24;q11) T-ALL. These findings suggest that homeobox-containing genes that normally act as transcription factors may contribute to T-cell leukemogenesis when abnormally expressed.

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