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)

The model of erythroleukemia caused by Spi-1/PU.1 transgenesis in mice is a multistage disease. A preleukemic step is characterized by an acute proliferation of proerythroblasts due to the arrest of differentiation provoked by Spi-1/PU.1. Later on, a blastic crisis occurs associated with somatic oncogenic mutations in the stem cell factor (SCF) receptor kit. To gain insights into the mechanisms of the leukemic progression, we performed proteomic profiling analyses of proerythroblasts isolated at the 2 stages of the disease. Our results indicate that the level of ezrin, a membrane cytoskeletal crosslinker, is increased in the leukemic cells. We show that Kit oncogenic forms are responsible for ezrin phosphorylation and that phosphorylation rather than overexpression is essential in the leukemic proerythroblasts. Using expression of dominant-negative forms of ezrin, we show that phosphorylation of ezrin on residue Y353 participates in apoptosis resistance, whereas phosphorylation on residue Y145 promotes proliferation of the leukemic cells in vitro and in vivo. Another recurrent oncogenic form of tyrosine kinases (Flt3) most frequently involved in human myeloid leukemia was also able to phosphorylate ezrin. These findings point to a new role for ezrin as signaling player in the development of leukemia, being a downstream effector of oncogenic tyrosine kinases in leukemic blasts.
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PMID:Ezrin is a target for oncogenic Kit mutants in murine erythroleukemia. 1818 70

The transcription factor PU.1 is essential for terminal myeloid differentiation, B- and T-cell development, erythropoiesis and hematopoietic stem cell maintenance. PU.1 functions as oncogene in Friend virus-induced erythroleukemia and as tumor suppressor in acute myeloid leukemias. Moreover, Friend virus-induced erythroleukemia requires maintenance of PU.1 expression and the disruption of p53 function greatly accelerates disease progression. It has been hypothesized that p53-mediated expression of the p21(Cip1) cell cycle inhibitor during differentiation of pre-erythroleukemia cells promotes selection against p53 function. In addition to the blockage of erythroblast differentiation provided by increased levels of PU.1, we propose that PU.1 alters p53 function. We demonstrate that PU.1 reduces the transcriptional activity of the p53 tumor suppressor family and thus inhibits activation of genes important for cell cycle regulation and apoptosis. Inhibition is mediated through binding of PU.1 to the DNA-binding and/or oligomerization domains of p53/p73 proteins. Lastly, knocking down endogenous PU.1 in p53 wild-type REH B-cell precursor leukemia cells leads to increased expression of the p53 target p21(Cip1).
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PMID:PU.1 binding to the p53 family of tumor suppressors impairs their transcriptional activity. 1819 90

Plasmacytoid dendritic cells (pDCs) are involved in innate immunity (eg, by secreting interferons) and also give rise to CD4+CD56+ hematodermic neoplasms. We report extensive characterization of human pDCs in routine tissue samples, documenting the expression of 19 immunohistologic markers, including signaling molecules (eg, BLNK), transcription factors (eg, ICSBP/IRF8 and PU.1), and Toll-like receptors (TLR7, TLR9). Many of these molecules are expressed in other cell types (principally B cells), but the adaptor protein CD2AP was essentially restricted to pDCs, and is therefore a novel immunohistologic marker for use in tissue biopsies. We found little evidence for activation-associated morphologic or phenotypic changes in conditions where pDCs are greatly increased (eg, Kikuchi disease). Most of the molecules were retained in the majority of pDC neoplasms, and 3 (BCL11A, CD2AP, and ICSBP/IRF8) were also commonly negative in leukemia cutis (acute myeloid leukemia in the skin), a tumor that may mimic pDC neoplasia. In summary, we have documented a range of molecules (notably those associated with B cells) expressed by pDCs in tissues and peripheral blood (where pDCs were detectable in cytospins at a frequency of <1% of mononuclear cells) and also defined potential new markers (in particular CD2AP) for the diagnosis of pDC tumors.
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PMID:Novel markers of normal and neoplastic human plasmacytoid dendritic cells. 1821 51

RUNX1/AML1 is required for the development of definitive hematopoiesis, and its activity is altered by mutations, deletions, and chromosome translocations in human acute leukemia. RUNX1 function can be regulated by post-translational modifications and protein-protein interactions. We show that RUNX1 is arginine-methylated in vivo by the arginine methyltransferase PRMT1, and that PRMT1 serves as a transcriptional coactivator for RUNX1 function. Using mass spectrometry, and a methyl-arginine-specific antibody, we identified two arginine residues (R206 and R210) within the region of RUNX1 that interact with the corepressor SIN3A and are methylated by PRMT1. PRMT1- dependent methylation of RUNX1 at these arginine residues abrogates its association with SIN3A, whereas shRNA against PRMT1 (or use of a methyltransferase inhibitor) enhances this association. We find arginine-methylated RUNX1 on the promoters of two bona fide RUNX1 target genes, CD41 and PU.1 and show that shRNA against PRMT1 or RUNX1 down-regulates their expression. These arginine methylation sites and the dynamic regulation of corepressor binding are lost in the leukemia-associated RUNX1-ETO fusion protein, which likely contributes to its dominant inhibitory activity.
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PMID:Methylation of RUNX1 by PRMT1 abrogates SIN3A binding and potentiates its transcriptional activity. 1831 80

The Ets transcription factor PU.1, encoded by the gene Sfpi1, functions in a concentration-dependent manner to promote myeloid and B-cell development and has been implicated in myeloid and lymphoid leukemias. To determine the consequences of reducing PU.1 concentration during hematopoiesis, we analyzed mice with two distinct hypomorphic alleles of Sfpi1 that produce PU.1 at approximately 20% (BN) or approximately 2% (Blac) of wild-type levels. Myeloid development was impaired in these mice, but less severely than in Sfpi1 null mice. To identify the downstream target genes that respond to changes in PU.1 concentration, we analyzed ex vivo interleukin-3 dependent myeloid cell lines established from Sfpi1(BN/BN), Sfpi1(Blac/Blac) and Sfpi1(-/-) fetal liver cells. Unexpectedly, many T-cell and natural killer cell genes were expressed in Sfpi1(-/-) cells and repressed in a dose-dependent manner in Sfpi1(Blac/Blac) and Sfpi1(BN/BN) cells. This pattern of dose-dependent T/NK-cell gene repression also occurred in ex vivo interleukin-7 dependent progenitor B cell lines. These results suggest that PU.1 functions in a concentration-dependent manner to repress T-cell and natural killer cell fates while promoting myeloid and B-cell fates.
Leukemia 2008 Jun
PMID:Dose-dependent repression of T-cell and natural killer cell genes by PU.1 enforces myeloid and B-cell identity. 1835 87

Hematopoietic malignancies are frequently associated with DNA hypomethylation but the molecular mechanisms involved in tumor formation remain poorly understood. Here we report that mice lacking Lsh develop leukemia associated with DNA hypomethylation and oncogene activation. Lsh is a member of the SNF2 chromatin remodeling family and is required for de novo methylation of genomic DNA. Mice that received Lsh deficient hematopoietic progenitors showed severe impairment of hematopoiesis, suggesting that Lsh is necessary for normal hematopoiesis. A subset of mice developed erythroleukemia, a tumor that does not spontaneously occur in mice. Tumor tissues were CpG hypomethylated and showed a modest elevation of the transcription factor PU.1, an oncogene that is crucial for Friend virus induced erythroleukemia. Analysis of Lsh(-/-) hematopoietic progenitors revealed widespread DNA hypomethylation at repetitive sequences and hypomethylation at specific retroviral elements within the PU.1 gene. Wild type cells showed Lsh and Dnmt3b binding at the retroviral elements located within the PU.1 gene. On the other hand, Lsh deficient cells had no detectable Dnmt3b association suggesting that Lsh is necessary for recruitment of Dnmt3b to its target. Furthermore, Lsh(-/-) hematopoietic precursors showed impaired suppression of retroviral elements in the PU.1 gene, an increase of PU.1 transcripts and protein levels. Thus DNA hypomethylation caused by Lsh depletion is linked to transcriptional upregulation of retroviral elements and oncogenes such as PU.1 which in turn may promote the development of erythroleukemia in mice.
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PMID:DNA hypomethylation caused by Lsh deletion promotes erythroleukemia development. 1848 51

Osteolytic bone disease in multiple myeloma (MM) is caused by enhanced osteoclast (OCL) activation and inhibition of osteoblast function. Lenalidomide and bortezomib have shown promising response rates in relapsed and newly diagnosed MM, and bortezomib has recently been reported to inhibit OCLs. We here investigated the effect of lenalidomide on OCL formation and osteoclastogenesis in comparison with bortezomib. Both drugs decreased alpha V beta 3-integrin, tartrate-resistant acid phosphatase-positive cells and bone resorption on dentin disks. In addition, both agents decreased receptor activator of nuclear factor-kappaB ligand (RANKL) secretion of bone marrow stromal cells (BMSCs) derived from MM patients. We identified PU.1 and pERK as major targets of lenalidomide, and nuclear factor of activated T cells of bortezomib, resulting in inhibition of osteoclastogenesis. Furthermore, downregulation of cathepsin K, essential for resorption of the bone collagen matrix, was observed. We demonstrated a significant decrease of growth and survival factors including macrophage inflammatory protein-alpha, B-cell activating factor and a proliferation-inducing ligand. Importantly, in serum from MM patients treated with lenalidomide, the essential bone-remodeling factor RANKL, as well as the RANKL/OPG ratio, were significantly reduced, whereas osteoprotegerin (OPG) was increased. We conclude that both agents specifically target key factors in osteoclastogenesis, and could directly affect the MM-OCL-BMSCs activation loop in osteolytic bone disease.
Leukemia 2008 Oct
PMID:Lenalidomide inhibits osteoclastogenesis, survival factors and bone-remodeling markers in multiple myeloma. 1859 40

The transcription factor PU.1 is an important regulator of hematopoiesis; precise expression levels are critical for normal hematopoietic development and suppression of leukemia. We show here that noncoding antisense RNAs are important modulators of proper dosages of PU.1. Antisense and sense RNAs are regulated by shared evolutionarily conserved cis-regulatory elements, and we can show that antisense RNAs inhibit PU.1 expression by modulating mRNA translation. We propose that such antisense RNAs will likely be important in the regulation of many genes and may be the reason for the large number of overlapping complementary transcripts with so far unknown function.
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PMID:PU.1 expression is modulated by the balance of functional sense and antisense RNAs regulated by a shared cis-regulatory element. 1867 13

Although leukemogenic tyrosine kinases (LTKs) activate a common set of downstream molecules, the phenotypes of leukemia caused by LTKs are rather distinct. Here we report the molecular mechanism underlying the development of hypereosinophilic syndrome/chronic eosinophilic leukemia by FIP1L1-PDGFRalpha. When introduced into c-Kit(high)Sca-1(+)Lineage(-) cells, FIP1L1-PDGFRalpha conferred cytokine-independent growth on these cells and enhanced their self-renewal, whereas it did not immortalize common myeloid progenitors in in vitro replating assays and transplantation assays. Importantly, FIP1L1-PDGFRalpha but not TEL-PDGFRbeta enhanced the development of Gr-1(+)IL-5Ralpha(+) eosinophil progenitors from c-Kit(high)Sca-1(+)Lineage(-) cells. FIP1L1-PDGFRalpha also promoted eosinophil development from common myeloid progenitors. Furthermore, when expressed in megakaryocyte/erythrocyte progenitors and common lymphoid progenitors, FIP1L1-PDGFRalpha not only inhibited differentiation toward erythroid cells, megakaryocytes, and B-lymphocytes but aberrantly developed eosinophil progenitors from megakaryocyte/erythrocyte progenitors and common lymphoid progenitors. As for the mechanism of FIP1L1-PDGFRalpha-induced eosinophil development, FIP1L1-PDGFRalpha was found to more intensely activate MEK1/2 and p38(MAPK) than TEL-PDGFRbeta. In addition, a MEK1/2 inhibitor and a p38(MAPK) inhibitor suppressed FIP1L1-PDGFRalpha-promoted eosinophil development. Also, reverse transcription-PCR analysis revealed that FIP1L1-PDGFRalpha augmented the expression of C/EBPalpha, GATA-1, and GATA-2, whereas it hardly affected PU.1 expression. In addition, short hairpin RNAs against C/EBPalpha and GATA-2 and GATA-3KRR, which can act as a dominant-negative form over all GATA members, inhibited FIP1L1-PDGFRalpha-induced eosinophil development. Furthermore, FIP1L1-PDGFRalpha and its downstream Ras inhibited PU.1 activity in luciferase assays. Together, these results indicate that FIP1L1-PDGFRalpha enhances eosinophil development by modifying the expression and activity of lineage-specific transcription factors through Ras/MEK and p38(MAPK) cascades.
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PMID:FIP1L1-PDGFRalpha imposes eosinophil lineage commitment on hematopoietic stem/progenitor cells. 1914 1

In the acute promyelocytic leukemia (APL) bearing the t(15;17), all-trans-retinoic acid (ATRA) treatment induces granulocytic maturation and complete remission of leukemia. We identified miR-342 as one of the microRNAs (miRNAs) upregulated by ATRA during APL differentiation. This miRNA emerged as a direct transcriptional target of the critical hematopoietic transcription factors PU.1 and interferon regulatory factor (IRF)-1 and IRF-9. IRF-1 maintains miR-342 at low levels, whereas the binding of PU.1 and IRF-9 in the promoter region following retinoic ATRA-mediated differentiation, upregulates miR-342 expression. Moreover, we showed that enforced expression of miR-342 in APL cells stimulated ATRA-induced differentiation. These data identified miR-342 as a new player in the granulocytic differentiation program activated by ATRA in APL.
Leukemia 2009 May
PMID:A new molecular network comprising PU.1, interferon regulatory factor proteins and miR-342 stimulates ATRA-mediated granulocytic differentiation of acute promyelocytic leukemia cells. 1915 78


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