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Structure and expression of the human trithorax-like gene 1 involved in acute leukemias.

ABSTRACT: The human trithorax-like gene 1 (Htrx1 gene) is disrupted in 11q23 translocations that are associated with acute leukemias. Sequencing of a partial human cDNA revealed an open reading frame encoding 1012 amino acids with extensive homology to the Drosophila trithorax protein, particularly in the zinc finger-like domains. Htrx1 gene appears to be unique in the human genome and has been conserved during evolution. Use of the human cDNA as a probe demonstrates that this gene is interrupted in both infant and adult acute myeloid (AML) and lymphoid (ALL) leukemia patients with 11q23 translocations. The structure of the Htrx1 gene around the breakpoints shows that this part of the human gene is interrupted by nine introns. As a result of the rearrangement, zinc finger domains are translocated in both ALL and AML patients. Expression studies reveal that the Htrx1 gene differentially expresses three transcripts within the normal lymphocyte cell lineage.

SUBMITTER: Parry P

PROVIDER: S-EPMC46588 | biostudies-other | 1993 May

REPOSITORIES: biostudies-other

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Structure and expression of the human trithorax-like gene 1 involved in acute leukemias.

Parry P P Djabali M M Bower M M Khristich J J Waterman M M Gibbons B B Young B D BD Evans G G

Proceedings of the National Academy of Sciences of the United States of America 19930501 10

The human trithorax-like gene 1 (Htrx1 gene) is disrupted in 11q23 translocations that are associated with acute leukemias. Sequencing of a partial human cDNA revealed an open reading frame encoding 1012 amino acids with extensive homology to the Drosophila trithorax protein, particularly in the zinc finger-like domains. Htrx1 gene appears to be unique in the human genome and has been conserved during evolution. Use of the human cDNA as a probe demonstrates that this gene is interrupted in both ...[more]

PMID: 8506328

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Project description:The most frequent targets of genetic alterations in human leukemias are transcription factor genes with essential functions in normal blood cell development. The Interferon Regulatory Factor 4 (IRF4) gene encodes a transcription factor important for key developmental stages of hematopoiesis, with known oncogenic implications in multiple myeloma, adult leukemias and lymphomas. Very few studies have reported an association of IRF4 with childhood malignancy, whereas high transcript levels have been observed in the more mature immunophenotype of ALL. Our aim was to investigate the expression levels of IRF4 in the diagnostic samples of pediatric leukemias and compare them to those of healthy controls, in order to determine aberrant gene expression and whether it extends to leukemic subtypes other than the relatively mature ALL subpopulation. Quantitative real-time RT-PCR methodology was used to investigate IRF4 expression in 58 children with acute leukemias, 4 leukemic cell lines and 20 healthy children. We show that aberrant IRF4 gene expression is implicated in a variety of leukemic subtypes; higher transcript levels appear in the more immature B-common ALL subtype and in T-cell than in B-cell leukemias, with the highest expression levels appearing in the AML group. Interestingly, we show that childhood leukemia, irrespective of subtype or cell maturation stage, is characterised by a minimum of approximately twice the amount of IRF4 gene expression encountered in healthy children. A statistically significant correlation also appeared to exist between high IRF4 expression and relapse. Our results show that ectopic expression of IRF4 follows the reverse expression pattern of what is encountered in normal B-cell development and that there might be a dose-dependency of childhood leukemia for aberrantly expressed IRF4, a characteristic that could be explored therapeutically. It is also suggested that high IRF4 expression might be used as an additional prognostic marker of relapse at diagnosis.

Project description:MicroRNAs (miRNAs) are small ( approximately 22 nucleotide) non-coding RNAs whose altered expression has been associated with various types of cancers, including leukemia. In the present study, we conducted a quantitative PCR (qPCR) analysis of expression of 23 human precursor miRNAs in bone marrow specimens of 85 Chinese primary leukemia patients, including 53 acute myeloid leukemia (AML) and 32 acute lymphoblastic leukemia (ALL) cases. We show that 16 miRNAs were differentially expressed between AMLs and ALLs. Of them, eight were previously reported (i.e., miR-23a, miR-27a/b, miR-128a, miR-128b, miR-221, miR-222, miR-223, and let-7b) and eight were newly identified (i.e., miR-17, miR-20a, miR-29a/c, miR-29b, miR-146a, miR-150, miR-155, and miR-196b). More importantly, through correlating miRNA expression signatures with outcome of patients, we further show that expression signatures of a group of miRNAs are associated with overall survival of patients. Of them, three (i.e., miR-146a, miR-181a/c, and miR-221), five (i.e., miR-25, miR-26a, miR-29b, miR-146a, and miR-196b), and three (i.e., miR-26a, miR-29b, and miR-146a) miRNAs are significantly associated with overall survival (P<0.05) of the 32 ALL, 53 AML, and 40 non-M3 AML patients, respectively. Particularly, the expression signature of miR-146a is significantly inversely correlated with overall survival of both ALL and AML patients. The prognostic significance of miR-146a in AML has been confirmed further in an independent study of 61 Chinese new AML patient samples. We also identified 622 putative target genes of miR-146a that are predicted by at least three out of the five major prediction programs (i.e., TragetScan, PicTar, miRanda, miRBase Targets, and PITA). Through gene ontology analysis, we found that these genes were particularly enriched (2- to 9-fold higher than expected by chance) in the GO categories of "negative regulation of biology processes," "negative regulation of cellular processes," "apoptosis," and "cell cycle," which may be related to the association of miR-146a with poor survival.

Dataset Information

Structure and expression of the human trithorax-like gene 1 involved in acute leukemias.

Publications

Structure and expression of the human trithorax-like gene 1 involved in acute leukemias.

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