Inhibition of Granulocyte-Macrophage Colony-Stimulating Factor Signaling and Microglial Proliferation by Anti-CD45RO: Role of Hck Tyrosine Kinase and Phosphatidylinositol 3-Kinase/Akt

Suh, Hyeon-Sook; Kim, Mee-Ohk; Lee, Sunhee C.

doi:10.4049/jimmunol.174.5.2712

Cited by 81 publications

(74 citation statements)

References 76 publications

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“…Among the common targets of microarray and ChIP-chip assays, approximately 30% show human t(8;21)-specific up or down-regulation compared with AML that have other chromosomal abnormalities. CD45, a protein tyrosine phosphatase and a negative regulator of cytokine/growth factor receptor and JAK/STAT signaling, [21][22][23] is among those targets. Its expression is down-regulated in AE9a leukemia cells.…”

Section: Introductionmentioning

confidence: 99%

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Combined gene expression and DNA occupancy profiling identifies potential therapeutic targets of t(8;21) AML

Peterson

Yan

et al. 2012

Blood

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IntroductionAcute myeloid leukemia (AML) is a common hematologic malignancy characterized by an abnormal accumulation of myeloid precursors in the bone marrow and blood. Similar to many other types of cancer, genetic abnormalities are associated with the development of AML, particularly chromosomal translocations that result in novel fusion proteins. One of the common translocations implicated in AML is the 8q22;21q22 translocation [t(8;21)]. 1 Based on the French-American-British (FAB) classification of leukemic cells, t(8;21) is associated with nearly 40% of the AML cases with the FAB M2 phenotype. 2 t(8,21) involves the AML1 (RUNX1) gene on chromosome 21 and the ETO (MTG8, RUNX1T1) gene on chromosome 8. [3][4][5] AML1 is the DNA-binding subunit of the core binding factor (CBF) transcription factor complex. Its N-terminus contains a highly conserved DNA binding domain called the runt homology domain (RHD). t(8;21) fuses the N-terminus of AML1 including RHD in-frame with almost the entire ETO protein to form AML1-ETO. [3][4][5][6] This fusion protein acts as a dominant negative form of AML1 during embryogenesis. 7,8 It functions as a transcriptional repressor by interacting with NCoR/SMRT/HDAC. 9,10 AML1-ETO was shown to activate expression of BCL-2 and p21, possibly via interacting with p300. [11][12][13] AML1-ETO promotes stem cell renewal and blocks hematopoietic differentiation. [14][15][16] However, its role in blocking cell-cycle progression and promoting apoptosis contradicts its function in promoting leukemogenesis and therefore requires secondary mutagenic events for full transformation. 17,18 We previously identified a single nucleotide insertion that resulted in a truncated AML1-ETO protein (AML1-ETOtr or AEtr), which rapidly promoted leukemia. 19 Subsequently, we identified a C-terminally truncated variant of AML1-ETO named AML1-ETO9a (AE9a), resulting from alternative splicing and found to coexist with full-length AML1-ETO in most analyzed t(8;21) AML patients. 20 Similar to AEtr, AE9a causes a rapid onset of leukemia in mice, 20 which provides a useful mouse model to study the molecular biology of t(8;21) leukemia.To understand the molecular mechanism of AML1-ETOrelated leukemia development and to explore novel therapeutic targets to treat this type of leukemia, in this study we combined gene expression microarray and promoter occupancy (ChIP-chip) analyses to identify genes directly modulated by AE9a in primary murine leukemia cells. Among the common targets of microarray and ChIP-chip assays, approximately 30% show human t(8;21)-specific up or down-regulation compared with AML that have other chromosomal abnormalities. CD45, a protein tyrosine phosphatase and a negative regulator of cytokine/growth factor receptor and JAK/STAT signaling, 21-23 is among those targets. Its expression is down-regulated in AE9a leukemia cells. Consequently, JAK/STAT signaling is enhanced in these leukemia cells. We show that re-expression of CD45 suppresses JAK/STAT activation, delays leukemia development by AE9a an...

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Section: Introductionmentioning

confidence: 99%

“…Furthermore, CD45 is a transmembrane protein tyrosine phosphatase involved in the negative regulation of cytokine/growth factor receptor and JAK/STAT signaling. [21][22][23] Therefore, the downregulation of CD45 may lead to enhanced JAK/STAT signaling, which is implicated in myeloid and lymphoid hematologic malignancies. 39…”

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confidence: 99%

Combined gene expression and DNA occupancy profiling identifies potential therapeutic targets of t(8;21) AML

Peterson

Yan

et al. 2012

Blood

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“…5 This may reflect a decrease in fitness advantage for downmodulating MHC Class I in brain, perhaps due to its lower expression on ramified microglia 20 or reduced CTL selection pressure in the brain compared to lymphoid tissue, and possibly an increase in the fitness advantage for altering the composition of the T cell epitope in this domain. Adaptive mutations also occurred within a motif potentially involved in Nef-mediated Hck activation, which may enhance replication and pathogenesis by increasing the promoter activity of the HIV LTR, 21 inducing proliferation of infected microglia 22 and=or dysregulating the immune response by altering macrophage phagocytosis and chemotaxis. 23 Evidence of viral adaptive selection at the divergence between lymphoid and brain nef sequences implies that brain-derived nef sequences adaptively evolve to enhance viral replication in brain macrophages and microglia and escape brain-specific immune surveillance.…”

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confidence: 99%

Evidence for Adaptive Evolution at the Divergence Between Lymphoid and Brain HIV-1nefGenes

Olivieri

Agopian

Mukerji

et al. 2010

AIDS Research and Human Retroviruses

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Human immunodeficiency virus type 1 (HIV) infection of the central nervous system frequently causes HIVassociated neurocognitive disorders (HAND). The role of HIV Nef and other accessory proteins in HAND pathogenesis is unclear. To determine whether HIV nef undergoes adaptive selection in brain, we cloned 100 nef sequences (n ¼ 30 brain and n ¼ 70 lymphoid) from four patients with AIDS and HIV-associated dementia (HAD). Normalized nonsynonymous substitutions were more frequent at the divergence of lymphoid and brain sequences, indicating stronger adaptive selection in brain compared to lymphoid tissue. Brain-specific nonsynonymous substitutions were found within an NH 3 -terminal CTL epitope, the PACS1 binding motif, or positions predicted to be important for activation of the myeloid-restricted Src family tyrosine kinase Hck. These results suggest that adaptive selection of HIV nef in brain may reflect altered requirements for efficient replication in macrophages and brain-specific immune selection pressures.

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“…Microglia proliferation is regulated by density-dependent inhibition and GM-CSF (6), which controls proliferation by various cell cycle-associated proteins (7), phosphorylation of MAPKs, and translocation of STAT5 to the nucleus (8) and activation of tyrosine kinases (9). Cytokines, such as IL-1␤ and TNF-␣, which are produced in a variety of CNS pathologies (10), have numerous functions, including stimulation of microglia proliferation (11,12) and reactive oxygen species (ROS) 3 production in the periphery (13,14).…”

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confidence: 99%

Microglia Proliferation Is Regulated by Hydrogen Peroxide from NADPH Oxidase

Mander

Jekabsone

Brown

2006

The Journal of Immunology

182

142

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Microglia are resident brain macrophages that become activated and proliferate following brain damage or stimulation by immune mediators, such as IL-1β or TNF-α. We investigated the mechanisms by which microglial proliferation is regulated in primary cultures of rat glia. We found that basal proliferation of microglia was stimulated by proinflammatory cytokines IL-1β or TNF-α, and this proliferation was completely inhibited by catalase, implicating hydrogen peroxide as a mediator of proliferation. In addition, inhibitors of NADPH oxidase (diphenylene iodonium or apocynin) also prevented microglia proliferation, suggesting that this may be the source of hydrogen peroxide. IL-1β and TNF-α rapidly stimulated the rate of hydrogen peroxide produced by isolated microglia, and this was inhibited by diphenylene iodonium, implying that the cytokines were acting directly on microglia to stimulate the NADPH oxidase. Low concentrations of PMA or arachidonic acid (known activators of NADPH oxidase) or xanthine/xanthine oxidase or glucose oxidase (generating hydrogen peroxide) also increased microglia proliferation and this was blocked by catalase, showing that NADPH oxidase activation or hydrogen peroxide was sufficient to stimulate microglia proliferation. In contrast to microglia, the proliferation of astrocytes was unaffected by the presence of catalase. In conclusion, these findings indicate that microglial proliferation in response to IL-1β or TNF-α is mediated by hydrogen peroxide from NADPH oxidase.

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Inhibition of Granulocyte-Macrophage Colony-Stimulating Factor Signaling and Microglial Proliferation by Anti-CD45RO: Role of Hck Tyrosine Kinase and Phosphatidylinositol 3-Kinase/Akt

Cited by 81 publications

References 76 publications

Combined gene expression and DNA occupancy profiling identifies potential therapeutic targets of t(8;21) AML

Combined gene expression and DNA occupancy profiling identifies potential therapeutic targets of t(8;21) AML

Evidence for Adaptive Evolution at the Divergence Between Lymphoid and Brain HIV-1nefGenes

Microglia Proliferation Is Regulated by Hydrogen Peroxide from NADPH Oxidase

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