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)

Overexpression of the polycomb group gene Bmi1 promotes cell proliferation and induces leukaemia through repression of Cdkn2a (also known as ink4a/Arf) tumour suppressors. Conversely, loss of Bmi1 leads to haematological defects and severe progressive neurological abnormalities in which de-repression of the ink4a/Arf locus is critically implicated. Here, we show that Bmi1 is strongly expressed in proliferating cerebellar precursor cells in mice and humans. Using Bmi1-null mice we demonstrate a crucial role for Bmi1 in clonal expansion of granule cell precursors both in vivo and in vitro. Deregulated proliferation of these progenitor cells, by activation of the sonic hedgehog (Shh) pathway, leads to medulloblastoma development. We also demonstrate linked overexpression of BMI1 and patched (PTCH), suggestive of SHH pathway activation, in a substantial fraction of primary human medulloblastomas. Together with the rapid induction of Bmi1 expression on addition of Shh or on overexpression of the Shh target Gli1 in cerebellar granule cell cultures, these findings implicate BMI1 overexpression as an alternative or additive mechanism in the pathogenesis of medulloblastomas, and highlight a role for Bmi1-containing polycomb complexes in proliferation of cerebellar precursor cells.
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PMID:Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas. 1502 99

The human L3MBTL gene is located in 20q12, a region that is commonly deleted in myeloproliferative disorders (MPD), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML). L3MBTL is highly homologous to the D-lethal(3) malignant brain tumor [D-l(3)mbt] gene, which is a putative tumor-suppressor gene (TSG) identified in Drosophila and which is closely related to the Drosophila sex combs on midleg (SCM) protein, a member of the Polycomb group (PcG) family of transcriptional repressors. To examine whether L3MBTL functions as a "classic" TSG in human hematologic malignancies, we screened a panel of 17 myeloid leukemia cell lines and peripheral blood or bone marrow samples from 29 MDS and 13 MPD patients for mutations in the entire L3MBTL coding sequence, including intron/exon splice junctions. No mutations were identified, although two single nucleotide differences were found (in intron 14 and in exon 15), which were interpreted as polymorphic changes. We used real-time RT-PCR to quantify the level of L3MBTL mRNA in various normal myeloid and lymphoid cell populations. L3MBTL is expressed in normal CD34+ bone marrow cells, and we found that the pattern of L3MBTL expression was similar to that of BMI1, a well-studied PcG gene with oncogenic activity, suggesting that L3MBTL and BMI1 may be co-regulated during hematopoiesis. The expression of L3MBTL mRNA in 30 of 35 cell lines and 13 of 15 AML samples was comparable to the level of L3MBTL expression in the normal cell populations. However, five leukemia cell lines showed no L3MBTL expression, and two of the AML samples showed aberrant L3MBTL expression. These data suggest that L3MBTL is not mutated in MDS or MPD. However, given the known dosage effects of PcG proteins in regulating gene expression, reduced or absent L3MBTL expression may be relevant in some cases of myeloid leukemia.
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PMID:Structural integrity and expression of the L3MBTL gene in normal and malignant hematopoietic cells. 1533 43

The t(10;11)(p13;q14-21) is found in T-ALL and acute myeloid leukemia and fuses CALM (Clathrin-Assembly protein-like Lymphoid-Myeloid leukaemia gene) to AF10. In order to gain insight into the transcriptional consequences of this fusion, microarray-based comparison of CALM-AF10+ vs CALM-AF10- T-ALL was performed. This analysis showed upregulation of HOXA5, HOXA9, HOXA10 and BMI1 in the CALM-AF10+ cases. Microarray results were validated by quantitative RT-PCR on an independent group of T-ALL and compared to mixed lineage leukemia-translocated acute leukemias (MLL-t AL). The overexpression of HOXA genes was associated with overexpression of its cofactor MEIS1 in CALM-AF10+ T-ALL, reaching levels of expression similar to those observed in MLL-t AL. Consequently, CALM-AF10+ T-ALL and MLL-t AL share a specific HOXA overexpression, indicating they activate common oncogenic pathways. In addition, BMI1, located close to AF10 breakpoint, was overexpressed only in CALM-AF10+ T-ALL and not in MLL-t AL. BMI1 controls cellular proliferation through suppression of the tumor suppressors encoded by the CDKN2A locus. This locus, often deleted in T-ALL, was conserved in CALM-AF10+ T-ALL. This suggests that decreased CDKN2A activity, as a result of BMI1 overexpression, contributes to leukemogenesis in CALM-AF10+ T-ALL. We propose to define a HOXA+ leukemia group composed of at least MLL-t, CALM-AF10 and HOXA-t AL, which may benefit from adapted management.
Leukemia 2005 Nov
PMID:CALM-AF10+ T-ALL expression profiles are characterized by overexpression of HOXA and BMI1 oncogenes. 1610 95

The Polycomb group (PcG) gene BMI1 is required for the proliferation and self-renewal of normal and leukemic stem cells. Overexpression of Bmi1 oncogene causes neoplastic transformation of lymphocytes and plays essential role in pathogenesis of myeloid leukemia. Another PcG protein, Ezh2, was implicated in metastatic prostate and breast cancers, suggesting that PcG pathway activation is relevant for epithelial malignancies. Whether an oncogenic role of the BMI1 and PcG pathway activation may be extended beyond the leukemia and may affect progression of solid tumors as well remains unknown. Here we demonstrate that activation of the BMI1 oncogene-associated PcG pathway plays an essential role in metastatic prostate cancer, thus mechanistically linking the pathogenesis of leukemia, self-renewal of stem cells, and prostate cancer metastasis. To characterize the functional status of the PcG pathway in metastatic prostate cancer, we utilized advanced cell- and whole animal-imaging technologies, gene and protein expression profiling, stable siRNA-gene targeting, and tissue microarray (TMA) analysis in relevant experimental and clinical settings. We demonstrate that in multiple experimental models of metastatic prostate cancer both BMI1 and Ezh2 genes are amplified and gene amplification is associated with increased expression of corresponding mRNAs and proteins. For the first time, we provide images of human prostate carcinoma metastasis precursor cells isolated from blood and shown to overexpress both BMI1 and Ezh2 oncoproteins. Consistent with the PcG pathway activation hypothesis, increased BMI1 and Ezh2 expression in metastatic cancer cells is associated with elevated levels of H2AubiK119 and H3metK27 histones. Quantitative immunofluorescence colocalization analysis and expression profiling experiments documented increased BMI1 and Ezh2 expression in clinical prostate carcinoma samples and demonstrated that high levels of BMI1 and Ezh2 expression are associated with markedly increased likelihood of therapy failure and disease relapse after radical prostatectomy. Gene-silencing analysis reveals that activation of the PcG pathway is mechanistically linked with highly malignant behavior of human prostate carcinoma cells and is essential for in vivo growth and metastasis of human prostate cancer. We conclude that the results of experimental and clinical analyses indicate the important biological role of the PcG pathway activation in metastatic prostate cancer. Our work suggests that the PcG pathway activation is a common oncogenic event in pathogenesis of metastatic solid tumors and provides justification for development of small molecule inhibitors of the PcG chromatin silencing pathway as a novel therapeutic modality for treatment of metastatic prostate cancer.
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PMID:Essential role for activation of the Polycomb group (PcG) protein chromatin silencing pathway in metastatic prostate cancer. 1696 37

Acute myeloid leukemia (AML) is a heterogeneous group of diseases with respect to biology and clinical course. Through genome-wide scanning, we can have an improvement of the diagnosis and assay system of AML. Microarray was performed for the identification of acute myeloid leukemia prognosis. We divided patients into two groups (good prognosis group, GPG and poor prognosis group, PPG) based on differences in the individual reactions to treatment. Gene expression profiles were analyzed using microarray. Among genes up-regulated at least two-fold and down-regulated at least 0.5-fold in HL-60, we chose three up-regulated genes (PPP2CA, ME3, and CCDN2) and three down-regulated genes (GLO1, ANXA2, and BMI1) and confirmed the expression of these six genes by RT-PCR. We created a leukemia-specific subclass microarray, based on the gene expression profiles. Clinical samples from the bone marrow of four patients were hybridized on this microarray. Among the genes selected by the microarray technology, NB4, silenced TRIB3 and overexpressed XRN2 were not differentiated in spite of treatment with ATRA. This indicates that XRN2 and TRIB3 play an important role in cell differentiation. These data provided an expression profile for the diagnosis and prognosis of AML patients and identified candidate genes that might allow the prognosis of AML through the relative comparison of the expression level of genes between GPG and PPG.
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PMID:Gene expression profile related to prognosis of acute myeloid leukemia. 1798 22

B cell-specific Moloney murine leukaemia virus integration site 1 (Bmi1), known as the first functional member of PcG (Polycomb Group) family, is supposed to be a key regulator of stem cell self-proliferation. In this study, we investigated its expression in testis and its impact on spermatogonia proliferation for better understanding of its role in spermatogenesis. Results showed that Bmi1 was expressed in undifferentiated spermatogonia (A(s), A(pr) and A(al) spermatogonia). Overexpression of BMI1 could promote spermatogonia proliferation, while repression of endogenous Bmi1 by RNAi resulted in inhibition of the proliferation.
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PMID:Expression localization of Bmi1 in mice testis. 1835 50

Previously, several individuals with X-linked SCID (SCID-X1) were treated by gene therapy to restore the missing IL-2 receptor gamma (IL2RG) gene to CD34+ BM precursor cells using gammaretroviral vectors. While 9 of 10 patients were successfully treated, 4 of the 9 developed T cell leukemia 31-68 months after gene therapy. In 2 of these cases, blast cells contained activating vector insertions near the LIM domain-only 2 (LMO2) proto-oncogene. Here, we report data on the 2 most recent adverse events, which occurred in patients 7 and 10. In patient 10, blast cells contained an integrated vector near LMO2 and a second integrated vector near the proto-oncogene BMI1. In patient 7, blast cells contained an integrated vector near a third proto-oncogene,CCND2. Additional genetic abnormalities in the patients' blast cells included chromosomal translocations, gain-of-function mutations activating NOTCH1, and copy number changes, including deletion of tumor suppressor gene CDKN2A, 6q interstitial losses, and SIL-TAL1 rearrangement. These findings functionally specify a genetic network that controls growth in T cell progenitors. Chemotherapy led to sustained remission in 3 of the 4 cases of T cell leukemia, but failed in the fourth. Successful chemotherapy was associated with restoration of polyclonal transduced T cell populations. As a result, the treated patients continued to benefit from therapeutic gene transfer.
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PMID:Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. 1868 85

The Philadelphia chromosome-positive blastoma, maintained by serial subcutaneous transplantation in nude mice, is a highly proliferating biological mass consisting of homogenous CD34(+)CD38(-) myeloblastoid cells. These cells newly evolved from pluripotent leukemia stem cells of chronic myeloid leukemia in the chronic phase. Therefore, this mass may provide a unique tool for better understanding cellular and molecular mechanisms of self-renewal of leukemia stem cells. In this paper, we demonstrated that intravenously injected blastoma cells can cause Ph+ blastic leukemia with multiple invasive foci in NOD/SCID mice but not in nude mice. In addition, using an in vitro culture system, we clearly showed that blastoma cell adhesion to OP9 stromal cells accelerates blastoma cell proliferation that is associated with up-regulation of BMI1 gene expression; increased levels of beta-catenin and the Notch1 intra-cellular domain; and changed the expression pattern of variant CD44 forms, which are constitutively expressed in these blastoma cells. These findings strongly suggest that adhesion of leukemic stem cells to stromal cells via CD44 might be indispensable for their cellular defense against attack by immune cells and for maintenance of their self-renewal ability.
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PMID:Adhesion-mediated self-renewal abilities of Ph+ blastoma cells. 2036 49

The major limitation for the development of curative cancer therapies has been an incomplete understanding of the molecular mechanisms driving cancer progression. Human models to study the development and progression of chronic myeloid leukemia (CML) have not been established. Here, we show that BMI1 collaborates with BCR-ABL in inducing a fatal leukemia in nonobese diabetic/severe combined immunodeficiency mice transplanted with transduced human CD34(+) cells within 4-5 months. The leukemias were transplantable into secondary recipients with a shortened latency of 8-12 weeks. Clonal analysis revealed that similar clones initiated leukemia in primary and secondary mice. In vivo, transformation was biased toward a lymphoid blast crisis, and in vitro, myeloid as well as lymphoid long-term, self-renewing cultures could be established. Retroviral introduction of BMI1 in primary chronic-phase CD34(+) cells from CML patients elevated their proliferative capacity and self-renewal properties. Thus, our data identify BMI1 as a potential therapeutic target in CML.
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PMID:BMI1 collaborates with BCR-ABL in leukemic transformation of human CD34+ cells. 2072 41

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder that is characterized by the presence of a fusion oncogene, BCR-ABL, which encodes a protein with constitutive tyrosine kinase activity. This activity causes excessive production of myeloid cells and their premature release into the circulation. The discovery of tyrosine kinase inhibitors marked a major advance in CML therapy, but these drugs cannot eradicate the disease because they are unable to kill the most primitive, quiescent leukemic stem cells. This review discusses current research in CML and attractive targets that have emerged with potential for eradicating the disease. Several new targets have recently been investigated as potential modulators in myeloid leukemia pathogenesis, including the multiple gene regulators miRNAs, the apparently leukemia-specific cell surface marker IL1RAP, transcription factors such as BMI1 and FOXOs, the tumor suppressors PML and PP2A, and the tyrosine kinase JAK2.
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PMID:In search of CML stem cells' deadly weakness. 2137 37


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