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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The E2A locus is a frequent target of chromosomal translocations in B-cell acute lymphoblastic leukemia (B-ALL). E2A encodes two products, E12 and E47, that are part of the basic helix-loop-helix (bHLH) family of transcription factors and are central in B lineage differentiation. E2A haplo-insufficiency hinders progression through three major checkpoints in B-cell development: commitment into the B lineage, at the pro-B to pre-B transition, and in the induction of immunoglobulin M (IgM) expression required for a functional BCR. These observations underscore the importance of E2A gene dosage in B-cell development. Here we show that a higher proportion of pro-B cells in E2A(+/-) mice is in the cell cycle compared to that in wild-type littermates. This increase correlates with lower p21(waf/cip1) levels, indicating that E2A has an antiproliferative function in B-cell progenitors. Ectopic expression in the B lineage of SCL/Tal1, a tissue-specific bHLH factor that inhibits E2A function, blocks commitment into the B lineage without affecting progression through later stages of differentiation. Furthermore, ectopic SCL expression exacerbates E2A haplo-insufficiency in B-cell differentiation, indicating that SCL genetically interacts with E2A. Taken together, these observations provide evidence for a gradient of E2A activity that increases from the pre-pro-B to the pre-B stage and suggest a model in which low levels of E2A (as in pro-B cells) are sufficient to control cell growth, while high levels (in pre-B cells) are required for cell differentiation. The antiproliferative function of E2A further suggests that in B-ALL associated with t(1;19) and t(17;19), the disruption of one E2A allele contributes to leukemogenesis, in addition to other anomalies induced by E2A fusion proteins.
Mol Cell Biol 2002 Feb
PMID:Gradient of E2A activity in B-cell development. 1178 64

Approximately 80% of children with acute lymphoblastic leukemia (ALL) can be cured with modern therapy. Despite this success, the number of cases of relapsed ALL remains greater than the number of new cases of most childhood cancers. New strategies are needed to develop curative therapy for the 20% of patients who are not being cured today, and to develop less toxic and less onerous treatment for ALL patients. Molecular genetics has already provided important insights to the mechanisms of leukemogenesis and is now routinely used to define the prognosis and guide treatment intensity for childhood ALL. Pharmacogenomics is a burgeoning field that aims to elucidate inherited differences in drug disposition and treatment response, toward individualizing therapy to enhance efficacy and reduce toxicity. Herein, we review recent progress in thesefields as they relate to childhood ALL, and discuss the promise they hold to further enhance treatment of the most common cancer in children.
Curr Opin Mol Ther 2001 Dec
PMID:Pharmacogenomics of childhood acute lymphoblastic leukemia. 1180 71

Constitutive NOTCH signaling in lymphoid progenitors promotes the development of immature T-cell lymphoblastic neoplasms (T-ALLs). Although it is clear that Notch signaling can initiate leukemogenesis, it has not previously been established whether continued NOTCH signaling is required to maintain T-ALL growth. We demonstrate here that the blockade of Notch signaling at two independent steps suppresses the growth and survival of NOTCH1-transformed T-ALL cells. First, inhibitors of presenilin specifically induce growth suppression and apoptosis of a murine T-ALL cell line that requires presenilin-dependent proteolysis of the Notch receptor in order for its intracellular domain to translocate to the nucleus. Second, a 62-amino-acid peptide derived from a NOTCH coactivator, Mastermind-like-1 (MAML1), forms a transcriptionally inert nuclear complex with NOTCH1 and CSL and specifically inhibits the growth of both murine and human NOTCH1-transformed T-ALLs. These studies show that continued growth and survival of NOTCH1-transformed lymphoid cell lines require nuclear access and transcriptional coactivator recruitment by NOTCH1 and identify at least two steps in the Notch signaling pathway as potential targets for chemotherapeutic intervention.
Mol Cell Biol 2003 Jan
PMID:Growth suppression of pre-T acute lymphoblastic leukemia cells by inhibition of notch signaling. 1250 63

The expression of both Notch3 and pre-T-cell-receptor (pre-TCR) invariant chain appears to be a common feature of all T-cell acute lymphoblastic leukemias (T-ALL). Notch genes, and other genes that are dysregulated in some T-ALL subgroups, encode factors that play a crucial role in both T-cell development and leukemogenesis. A complex network of signals, involving Notchs, pre-TCR, nuclear factor kappaB and E2A, appears to be responsible for the leukemogenesis process. Thus, T-ALL is a paradigm for developmental pathways that underlie the pathogenesis of this disease.
Trends Mol Med 2003 Jan
PMID:Notch, a unifying target in T-cell acute lymphoblastic leukemia? 1252 8

The (11;19)(q23;p13.1) translocation in acute leukemia results in the formation of a chimeric MLL-ELL fusion protein. ELL is an RNA Polymerase II (Pol II) transcriptional elongation factor that interacts with the recently identified EAF1 protein. Here, we show that ELL and EAF1 are components of Cajal bodies (CBs). Although ELL and EAF1 colocalize with p80 coilin, the signature protein of CBs, ELL and EAF1 do not exhibit a direct physical interaction with p80 coilin. Treatment of cells with actinomycin D, DRB, or alpha-amanitin, specific inhibitors of Pol II, disperses ELL and EAF1 from CBs, indicating that localization of ELL and EAF1 in CBs is dependent on active transcription by Pol II. The concentration of ELL and EAF1 in CBs links the transcriptional elongation activity of ELL to the RNA processing functions previously identified in CBs. Strikingly, CBs are disrupted in MLL-ELL leukemia. EAF1 and p80 coilin are delocalized from CBs in murine MLL-ELL leukemia cells and in HeLa cells transiently transfected with MLL-ELL. Nuclear and cytoplasmic fractionation revealed diminished expression of p80 coilin and EAF1 in the nuclei of MLL-ELL leukemia cells [corrected]. These studies are the first demonstration of a direct role of CB components in leukemogenesis.
Mol Biol Cell 2003 Apr
PMID:ELL and EAF1 are Cajal body components that are disrupted in MLL-ELL leukemia. 1268 6

The t(8;21) is one of the most frequent chromosomal translocations associated with acute leukemia. The translocation fuses the DNA binding domain of AML1 to nearly all of the ETO co-repressor. ETO associates with the mSin3 and N-CoR co-repressors as well as histone deacetylases 1, 2, and 3. Although this is one of the most frequent chromosomal translocations in acute leukemia, accounting for 10-15% of the cases of acute myeloid leukemia (AML), the direct targets for transcriptional regulation that stimulate leukemogenesis are unknown. We found that AML1-ETO repressed the promoter of p14(ARF) tumor suppressor in transient transfection assays and reduced endogenous levels of p14(ARF) expression in multiple cell types. Chromatin immunoprecipitation assays demonstrated that AML1-ETO bound to the p14(ARF) promoter. In acute myeloid leukemia samples containing the t(8;21), levels of p14(ARF) mRNA were markedly lower when compared to other acute myeloid leukemias. Therefore, p14(ARF) is a direct transcriptional target of AML1-ETO.
Blood Cells Mol Dis
PMID:The t(8;21) fusion protein contacts co-repressors and histone deacetylases to repress the transcription of the p14ARF tumor suppressor. 1273 81

We utilized a mouse model of acute promyelocytic leukemia (APL) to investigate how aberrant activation of cytokine signaling pathways interacts with chimeric transcription factors to generate acute myeloid leukemia. Expression in mice of the APL-associated fusion, PML-RARA, initially has only modest effects on myelopoiesis. Whereas treatment of control animals with interleukin-3 (IL-3) resulted in expanded myelopoiesis without a block in differentiation, PML-RARA abrogated differentiation that normally characterizes the response to IL-3. Retroviral transduction of bone marrow with an IL-3-expressing retrovirus revealed that IL-3 and promyelocytic leukemia-retinoic acid receptor alpha (PML-RARalpha) combined to generate a lethal leukemia-like syndrome in <21 days. We also observed that a constitutively activated mutant IL-3 receptor, beta(c)V449E, cooperated with PML-RARalpha in leukemogenesis, whereas a different activated mutant, beta(c)I374N, did not. Analysis of additional mutations introduced into beta(c)V449E showed that, although tyrosine phosphorylation of beta(c) is necessary for cooperation, the Src homology 2 domain-containing transforming protein binding site is dispensable. Our results indicate that chimeric transcription factors can block the differentiative effects of growth factors. This combination can be potently leukemogenic, but the particular manner in which these types of mutations interact determines the ability of such combinations to generate acute myeloid leukemia.
Mol Cell Biol 2003 Jul
PMID:Cooperation of cytokine signaling with chimeric transcription factors in leukemogenesis: PML-retinoic acid receptor alpha blocks growth factor-mediated differentiation. 1280 98

Transcription factor GATA-1 is essential for erythroid and megakaryocytic maturation. GATA-1 mutations are associated with hematopoietic precursor proliferation and leukemogenesis, suggesting a role in cell cycle control. While numerous GATA-1 target genes specifying mature hematopoietic phenotypes have been identified, how GATA-1 regulates proliferation remains unknown. We used a complementation assay based on synchronous inducible rescue of GATA-1(-) erythroblasts to show that GATA-1 promotes both erythroid maturation and G(1) cell cycle arrest. Molecular studies combined with microarray transcriptome analysis revealed an extensive GATA-1-regulated program of cell cycle control in which numerous growth inhibitors were upregulated and mitogenic genes were repressed. GATA-1 inhibited expression of cyclin-dependent kinase (Cdk) 6 and cyclin D2 and induced the Cdk inhibitors p18(INK4C) and p27(Kip1) with associated inactivation of all G(1) Cdks. These effects were dependent on GATA-1-mediated repression of the c-myc (Myc) proto-oncogene. GATA-1 inhibited Myc expression within 3 h, and chromatin immunoprecipitation studies indicated that GATA-1 occupies the Myc promoter in vivo, suggesting a direct mechanism for gene repression. Surprisingly, enforced expression of Myc prevented GATA-1-induced cell cycle arrest but had minimal effects on erythroid maturation. Our results illustrate how GATA-1, a lineage-determining transcription factor, coordinates proliferation arrest with cellular maturation through distinct, interrelated genetic programs.
Mol Cell Biol 2003 Jul
PMID:GATA-1-mediated proliferation arrest during erythroid maturation. 1283 87

To elucidate the role of mitogen-activated protein kinases (MAPKs) and Akt kinase in leukemogenesis caused by the breakpoint cluster region (BCR)-Abelson (ABL) tyrosine kinase oncoprotein, we examined the activities of MAPKs and Akt kinase and their roles in the action of STI571, a specific inhibitor of BCR-ABL tyrosine kinase, in chronic myelogenous leukemia (CML) cells. We found that extracellular signal-regulated kinase (ERK) 1/2 and Akt kinase are constitutively active in the chronic phase of CML, blast crisis of CML, and the CML-derived K562 cell line. Both interferon-alpha and STI571 suppressed ERK1/2 activity in K562 cells. In contrast, Akt kinase activity was inhibited only by STI571. K562 cell proliferation was markedly suppressed by LY294002, a specific inhibitor of PI3K/Akt kinase, and STI571 but not by PD98059, a specific inhibitor of MEK1/2. In addition, caspase-3 was activated by treatment of cells with STI571 and LY294002 but not with PD98059. These data indicate that Akt kinase may play a role in the proliferation of CML leukemia cells and the action of STI571. Primary leukemia cells from patients with CML blast crisis did not show inhibition of ERK1/2 or Akt kinase activity and were resistant to caspase-3-associated apoptosis after treatment with STI571. These findings suggest that STI571 does not effectively block signaling molecules downstream of the BCR-ABL tyrosine kinase in some cases of CML blast crisis.
Blood Cells Mol Dis
PMID:Involvement of Akt kinase in the action of STI571 on chronic myelogenous leukemia cells. 1285 Apr 78

Bcr-Abl is a dysregulated tyrosine kinase whose mechanism of activation is unclear. Here, we demonstrate that, like c-Abl, Bcr-Abl is negatively regulated through its SH3 domain. Kinase activity, transformation, and leukemogenesis by Bcr-Abl are greatly impaired by mutations of the Bcr coiled-coil domain that disrupt oligomerization, but restored by an SH3 point mutation that blocks ligand binding or a complementary mutation at the intramolecular SH3 binding site defined in c-Abl. Phosphorylation of tyrosines in the activation loop of the catalytic domain and the linker between the SH2 and catalytic domains (SH2-CD linker) is dependent on oligomerization and required for leukemogenesis. These results suggest that Bcr-Abl has a monomeric, unphosphorylated state with the SH3 domain engaged intramolecularly to Pro1124 in the SH2-CD linker, the form that is sensitive to the inhibitor imatinib (STI-571). The sole function of the coiled-coil domain is to disrupt the autoinhibited conformation through oligomerization and intermolecular autophosphorylation.
Mol Cell 2003 Jul
PMID:Autoinhibition of Bcr-Abl through its SH3 domain. 1288 90


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