Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Co-activation of Meisl with Hoxa7 or Hoxa9 homeobox genes by retroviral gene insertion has recently been reported to be leukemogenic in murine myeloid leukemia. In this study we determined their expression in human leukemia. Most human myeloid leukemia cell lines co-expressed MEIS1 with HOXA7 and HOXA9. Among patients with acute leukemia, 50% of AML patients expressed MEIS1, while the majority of ALL patients were negative. A total of 89.5% of patients expressing MEIS1 co-expressed HOXA7. In unadjusted models, poorer response to chemotherapy was associated with expression of HOXA7 regardless of MEIS1 status and older patients were more likely to express either gene.
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PMID:MEIS1 and HOXA7 genes in human acute myeloid leukemia. 1099 3

HOX genes encode transcription factors that control patterning and cell fates. Alterations in HOX expression have been clearly implicated in leukemia, but their role in most other malignant diseases remains unknown. By using degenerate reverse transcription-PCR and subsequent real-time quantitative assays, we examined HOX expression in lung cancer cell lines, direct tumor-control pairs, and bronchial epithelial cultures. As in leukemia, genes of the HOX9 paralogous group and HOXA10 were frequently overexpressed. For HOXB9, we confirmed that elevated RNA was associated with protein overexpression. In some cases, marked HOX overexpression was associated with elevated FGF10 and FGF17. During development, the WNT pathway affects cell fate, polarity, and proliferation, and WNT7a has been implicated in the maintenance of HOX expression. In contrast to normal lung and mortal short-term bronchial epithelial cultures, WNT7a was frequently reduced or absent in lung cancers. In immortalized bronchial epithelial cells, WNT7a was lost concomitantly with HOXA1, and a statistically significant correlation between the expression of both genes was observed in lung cancer cell lines. Furthermore, we identified a homozygous deletion of beta-catenin in the mesothelioma, NCI-H28, associated with reduced WNT7a and the lowest overall cell line expression of HOXA1, HOXA7, HOXA9, and HOXA10, whereas HOXB9 levels were unaffected. Of note, both WNT7a and beta-catenin are encoded on chromosome 3p, which undergoes frequent loss of heterozygosity in these tumors. Our results suggest that alterations in regulatory circuits involving HOX, WNT, and possibly fibroblast growth factor pathways occur frequently in lung cancer.
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PMID:Altered HOX and WNT7A expression in human lung cancer. 1107 89

The MLL gene is frequently rearranged in leukemias, and MLL chimeric proteins generated by chromosomal translocations play crucial roles in leukemogenesis. Targets of murine Mll include HOX proteins that regulate body pattern formation and hematopoiesis. However, it is not known whether or not the MLL chimeric proteins regulate the HOX gene expression in human leukemia. To address this issue, THP-1 cells, a human leukemia cell line expressing MLL-AF9, were treated with antisense oligodeoxyribonucleotide (ODN) complementary to the coding sequence of the MLL-AF9 junction. Down-regulation of the MLL-AF9 transcript was accompanied by the reduced expression of the HOXA7 and -A10 genes, but not of the HOXA2, -A4, -A5, and -A9 genes. The number of viable cells cultured with 20 microM antisense ODN for 5 days was 10-fold lower than that of the sense ODN-treated control. And the number of the annexin V-/propidium iodide- apoptotic cells in the antisense ODN-treated cells after 3 days of culture was two-fold higher than that in the control. Staining of the antisense ODN-treated cells with Hoechst 33258 showed the morphology characteristic to apoptosis. These results indicate that MLL-AF9 regulates the expression of the selected HOX genes as well as prevents the leukemic cells from apoptosis.
Leukemia 2001 Nov
PMID:Targeted down-regulation of MLL-AF9 with antisense oligodeoxyribonucleotide reduces the expression of the HOXA7 and -A10 genes and induces apoptosis in a human leukemia cell line, THP-1. 1168 16

We used a degenerate RT-PCR screen and subsequent real-time quantitative RT-PCR assays to examine the expression of HOX and TALE-family genes in 34 cases of chromosomally defined AML for which outcome data were available. AMLs with favorable cytogenetic features were associated with low overall HOX gene expression whereas poor prognostic cases had high levels. Characteristically, multiple HOXA family members including HOXA3-HOXA10 were jointly overexpressed in conjunction with HOXB3, HOXB6, MEIS1 and PBX3. Higher levels of expression were also observed in the FAB subtype, AML-M1. Spearmann correlation coefficients indicated that the expression levels for many of these genes were highly inter-related. While we did not detect any significant correlations between HOX expression and complete response rates or age in this limited set of patients, there was a significant correlation between event-free survival and HOXA7 with a trend toward significance for HoxA9, HoxA4 and HoxA5. While patients with elevated HOX expression did worse, there were notable exceptions. Thus, although HOX overexpression and clinical resistance to chemotherapy often coincide, they are not inextricably linked. Our results indicate that quantitative HOX analysis has the potential to add new information to the management of patients with AML, especially where characteristic chromosomal alterations are lacking.
Leukemia 2002 Feb
PMID:Quantitative HOX expression in chromosomally defined subsets of acute myelogenous leukemia. 1184 Feb 84

The chromosomal translocation t(4;11) marks infant acute lymphoblastic leukemia associated with a particularly dismal prognosis. The leukemogenic role of the corresponding fusion gene MLL-AF4 is not well understood. We show that transient inhibition of MLL-AF4 expression with small interfering RNAs impairs the proliferation and clonogenicity of the t(4; 11)-positive human leukemic cell lines SEM and RS4;11. Reduction of mixed-lineage leukemia (MLL)-ALL-1 fused gene from chromosome 4 (AF4) levels induces apoptosis associated with caspase-3 activation and diminished BCL-X(L) expression. Suppression of MLL-AF4 is paralleled by a decreased expression of the homeotic genes HOXA7, HOXA9, and MEIS1. MLL-AF4 depletion inhibits expression of the stem-cell marker CD133, indicating hematopoietic differentiation. Transfection of leukemic cells with MLL-AF4 siRNAs reduces leukemia-associated morbidity and mortality in SCID mice that received a xenotransplant, suggesting that MLL-AF4 depletion negatively affects leukemia-initiating cells. Our findings demonstrate that MLL-AF4 is important for leukemic clonogenicity and engraftment of this highly aggressive leukemia. Targeted inhibition of MLL-AF4 fusion gene expression may lead to an effective and highly specific treatment of this therapy-resistant leukemia.
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PMID:Targeting MLL-AF4 with short interfering RNAs inhibits clonogenicity and engraftment of t(4;11)-positive human leukemic cells. 1604 33

MLL/AF4 and AML/MTG8 represent two leukemic fusion genes, which are most frequently found in infant acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), respectively. We examined the influence of MLL/AF4 and AML1/MTG8 fusion genes on the expression of TERT coding for the telomerase protein subunit, and subsequently telomerase activity in t(4;11)-positive ALL and t(8;21)-positive cell lines, respectively. MLL/AF4 suppression diminished telomerase activity and expression of TERT. Blocking pro-apoptotic caspase activation in conjunction with MLL/AF4 knockdown enhanced the inhibition of TERT gene expression, which suggests that MLL/AF4 depletion does not reduce TERT expression levels by inducing apoptosis. Knockdown of HOXA7, a direct transcriptional target of MLL/AF4 fusion gene, caused a reduction of telomerase and TERT to an extent similar to that observed with MLL/AF4 suppression. Chromatin immunoprecipitation of SEM cells, using ectopically expressed FLAG-tagged Hoxa7, indicates HOXA7 binding site in the TERT promoter region. Furthermore, suppression of the AML1/MTG8 fusion gene was associated with severely reduced clonogenicity, induction of replicative senescence, impaired TERT expression and accelerated telomere shortening. We thus present findings that show a mechanistic link between leukemic fusion proteins, essential for development and maintenance of leukemia, and telomerase, a key element of both normal and malignant self-renewal.
Leukemia 2010 Oct
PMID:Leukemic fusion genes MLL/AF4 and AML1/MTG8 support leukemic self-renewal by controlling expression of the telomerase subunit TERT. 2068 4

Structural chromosomal rearrangements of the Nucleoporin 98 gene (NUP98), primarily balanced translocations and inversions, are associated with a wide array of hematopoietic malignancies. NUP98 is known to be fused to at least 28 different partner genes in patients with hematopoietic malignancies, including acute myeloid leukemia, chronic myeloid leukemia in blast crisis, myelodysplastic syndrome, acute lymphoblastic leukemia, and bilineage/biphenotypic leukemia. NUP98 gene fusions typically encode a fusion protein that retains the amino terminus of NUP98; in this context, it is important to note that several recent studies have demonstrated that the amino-terminal portion of NUP98 exhibits transcription activation potential. Approximately half of the NUP98 fusion partners encode homeodomain proteins, and at least 5 NUP98 fusions involve known histone-modifying genes. Several of the NUP98 fusions, including NUP98-homeobox (HOX)A9, NUP98-HOXD13, and NUP98-JARID1A, have been used to generate animal models of both lymphoid and myeloid malignancy; these models typically up-regulate HOXA cluster genes, including HOXA5, HOXA7, HOXA9, and HOXA10. In addition, several of the NUP98 fusion proteins have been shown to inhibit differentiation of hematopoietic precursors and to increase self-renewal of hematopoietic stem or progenitor cells, providing a potential mechanism for malignant transformation.
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PMID:NUP98 gene fusions and hematopoietic malignancies: common themes and new biologic insights. 2194 99

Although PBX proteins are known to increase DNA-binding/transcriptional activity of HOX proteins through their direct binding, the functional importance of their interaction in leukemogenesis is unclear.We recently reported that overexpression of a 4-homeobox-gene signature (ie, PBX3/HOXA7/HOXA9/HOXA11) is an independent predictor of poor survival in patients with cytogenetically abnormal acute myeloid leukemia (CA-AML). Here we show that it is PBX3, but not PBX1 or PBX2, that is consistently coexpressed with HOXA9 in various subtypes of CA-AML, particularly MLL-rearranged AML, and thus appears as a potential pathologic cofactor of HOXA9 in CA-AML. We then show that depletion of endogenous Pbx3 expression by shRNA significantly inhibits MLL-fusion-mediated cell transformation, and coexpressed PBX3 exhibits a significantly synergistic effect with HOXA9 in promoting cell transformation in vitro and leukemogenesis in vivo. Furthermore, as a proof of concept, we show that a small peptide, namely HXR9, which was developed to specifically disrupt the interactions between HOX and PBX proteins, can selectively kill leukemic cells with overexpression of HOXA/PBX3 genes. Collectively, our data suggest that PBX3 is a critical cofactor of HOXA9 in leukemogenesis, and targeting their interaction is a feasible strategy to treat presently therapy resistant CA-AML (eg, MLL-rearranged leukemia) in which HOXA/PBX3 genes are overexpressed.
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PMID:PBX3 is an important cofactor of HOXA9 in leukemogenesis. 2326 95

The mixed-lineage leukemia (MLL)-AF4 fusion protein encoded by the chromosomal translocation t(4;11) predicts a poorer prognosis in acute lymphoblastic leukemia (ALL) than in other MLL-associated leukemias. However, the detailed mechanism underlying regulation of MLL-AF4 expression remains largely unknown. In this study, we showed that microRNA (miR)-142-3p was significantly downregulated in ALL patients expressing MLL-AF4. Upregulation of miR-142-3p decreased MLL-AF4 expression in the RS4;11 leukemic cell line, which suggests that MLL-AF4 is a direct target of miR-142-3p. Ectopic expression of miR-142-3p remarkably suppressed cell proliferation and induced apoptosis in RS4;11 cells expressing the MLL-AF4 fusion protein. We also found that exogenous expression of miR-142-3p strongly reduced the expression of MLL-AF4 target genes such as homeobox A (HOXA)9, HOXA7, and HOXA10 in RS4;11 cells. Taken together, our results indicate that miR-142-3p functions as a growth suppressor in MLL-AF4(+) ALL, and its suppressive effects are mediated primarily through repression of MLL-AF4 expression.
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PMID:MicroRNA-142-3p inhibits cell proliferation in human acute lymphoblastic leukemia by targeting the MLL-AF4 oncogene. 2405 58

Leukemia is a malignant proliferative disease of blood system, which is caused by hyperplasia of white blood cells and infiltration into other tissues and organs with blood flow, leading to a series of clinical manifestations. In this study, we detected the expression of HOXA7 gene in human acute promyelocytic leukemia cell line NB4. The expression level of HOXA7 decreased in the presence of ATRA, which was able to inhibit the proliferation of NB4 cells. Furthermore, ATRA altered the morphology of NB4 cells. The study suggested that HOXA7 might be a new gene candidate that influences the maturation of acute myeloid leukemia, and provided the molecular basis for the treatment for acute promyelocyticleukemia.
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PMID:All-trans retinoic acid inhibits HOXA7 expression in leukemia cell NB4. 2682 89


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