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  • American Society of Hematology  (4)
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  • American Society of Hematology  (4)
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  • 1
    Online Resource
    Online Resource
    Aberrant Expression of Regulatory miRNAs and Transcripts for IRS-PI3K Growth and Survival Signaling In Waldenstrom's Macroglobulinemia
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 1912-1912
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 1912-1912
    Abstract: Abstract 1912 Background: Waldenstrom's Macroglobulinemia (WM) is a rare low grade non-Hodgkin's lymphoma characterized by the accumulation of IgM secreting lymphoplasmacytic cells in (LPC) the bone marrow, an elevated serum IgM, and frequently accompanied with hyperviscosity syndrome. The insulin receptor substrates (IRS) are important mediators of the insulin like receptor family and PI3K signaling leading to PKC and AKT activation. Methods: TaqMan low density arrays were used to evaluate the relative levels of 667 miRNAs in 11 WM patient and 5 age matched healthy donor (HD) CD19+ bone marrow cells. The results of this screen were validated using individual stem loop RT-PCR assays. Additional mRNA targets were identified using an existing gene expression profiling (GEP) data set of 22 WM patients and 8 HD using the Affymetrix U133 plus 2 platform. GEP findings were validated using an independent cohort of 18 WM patients and 7 HD. Results: Aberrant miRNAs identified were miR-21 (+3.27 fold p=0.035), miR-29c (+3.17 fold; p=0.003), miR-155 (+5.53 fold; p=0.082), miR-9* (-3.94 fold; p=0.001), miR-27b (-4.94 fold; p=0.001), miR-126 (-21.52 fold; p=0.006), miR-126* (-25.55 fold; p=0.039), miR-145 (-34.27 fold; p 〈 0.001), miR-223 (-24.25 fold; p=0.041), and miR-886-5p (-3.01 fold; p=0.004). Importantly, 5 of these 10 miRNAs targeted members of the IRS-PI3K signaling pathway, a pathway important for growth and survival of WM cells: miR-29c (PIK3R1); R-155 (SHIP1); miR-21 (PTEN); miR-145 (IRS1); miR-126 (IRS1 and PIK3R2), and predict for increased protein levels for PIK3R2 and IRS1 with lower protein levels for PIK3R1, PTEN and SHIP1. Moreover, GEP and confirmatory RT-PCR revealed down-regulation of the IRS-PI3K pathway members IRS2 (-2.0 fold; p=0.004) and PIK3R1 (-2.0 fold; p=0.04). Conclusions: The results of this demonstrate aberrant expression of regulatory miRNAs and transcripts for IRS-PI3K growth and survival signaling in WM, and provide support for the development of IRS/PI3K targeted therapeutics in WM. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.1912.1912
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
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    Online Resource
  • 2
    Online Resource
    Online Resource
    The Rituximab and IVIG Related IgM Flare In Waldenstrom's Macroglobulinemia Is Associated with Monocytic Activation of Fcgriia Signaling, and Triggering of IL-6 Release by the PI3K/AKT and MAPK Pathways
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 2870-2870
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 2870-2870
    Abstract: Abstract 2870 Background: We and others have previously reported a paradoxical flare in serum IgM levels following rituximab and/or IVIG administration which can occur within hours of its administration, and can affect 40–70% of WM patients. The paradoxical flare can often lead to symptomatic hyperviscosity, and/or aggravation of other IgM mediated morbidities. Direct stimulation of WM cells by rituximab or IVIG does not lead to further IgM release, and IL-6 levels rise in those patients experiencing a rituximab induced IgM flare (Yang et al, ASH 2009). We therefore sought to clarify the molecular mechanisms permitting the rituximab or IVIG mediated IgM flare in WM. Patients and Method: We performed co-culture studies of WM cells utilizing a transwell system with granulocytes or monocytes in the presence or absence of rituximab or IVIG. Granulocyte and monocyte cell lysates and supernatants were collected after rituximab stimulation for further analysis. IL-6 levels were assessed by multiplex assays and real-time RT-PCR. siRNAs targeting FcgRIA, FcgRIB, FcgRIIA, FcgRIIB, and FcgRIIIA were used to knockdown Fcγ receptors on primary monocytes. Fcγ receptor expression following siRNA transfection was confirmed by real-time RT-PCR and flow cytometry. Proteins from Rituximab stimulated monocytes were analyzed with phospho-antibody arrays and confirmed with western blotting. Results: A significant increase in IgM release was observed following co-culture of primary WM cells with monocytes and co-incubation with either rituximab or IVIG; was associated with IL-6 release, and could be blocked by anti-IL6 antibodies. The induction of IL-6 following rituximab stimulation of monocytes was significantly reduced following siRNA knockdown of FcgRIIA. Phospho-antibody array and ingenuity pathway analyses revealed that both PI3K/AKT and MAPK pathways were involved in signaling initiated by rituximab stimulation of monocytes through FcgRIIA. Increased phosphorylation of PI3K, AKT, p38MAPK and ERK1/2 was confirmed by western blotting with phospho-specific antibodies. In addition, inhibitors specific for PI3K, AKT, p38MAPK and ERK1/2 also reduced IL-6 production. Conclusion: Taken together, the above data suggest that the rituximab and/or IVIG related IgM flare observed in WM patients is triggered by IL-6 in response to stimulation of bystander monocytes through FcgRIIA binding and activation of the PI3K/AKT and MAPK pathways. Inhibitors aimed at these pathways block IL-6 release from rituximab stimulated monocytes. The results provided a framework for investigation of pre-emptive therapies for blocking the IgM flare in WM patients being considered for rituximab and/or IVIG therapy. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.2870.2870
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
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    Online Resource
  • 3
    Online Resource
    Online Resource
    A novel RIPK1 inhibitor reduces GVHD in mice via a nonimmunosuppressive mechanism that restores intestinal homeostasis
    American Society of Hematology ; 2023
    In:  Blood Vol. 141, No. 9 ( 2023-03-02), p. 1070-1086
    Details
    In: Blood, American Society of Hematology, Vol. 141, No. 9 ( 2023-03-02), p. 1070-1086
    Abstract: Intestinal epithelial cells (IECs) are implicated in the propagation of T-cell–mediated inflammatory diseases, including graft-versus-host disease (GVHD), but the underlying mechanism remains poorly defined. Here, we report that IECs require receptor-interacting protein kinase-3 (RIPK3) to drive both gastrointestinal (GI) tract and systemic GVHD after allogeneic hematopoietic stem cell transplantation. Selectively inhibiting RIPK3 in IECs markedly reduces GVHD in murine intestine and liver. IEC RIPK3 cooperates with RIPK1 to trigger mixed lineage kinase domain-like protein-independent production of T-cell–recruiting chemokines and major histocompatibility complex (MHC) class II molecules, which amplify and sustain alloreactive T-cell responses. Alloreactive T-cell–produced interferon gamma enhances this RIPK1/RIPK3 action in IECs through a JAK/STAT1-dependent mechanism, creating a feed-forward inflammatory cascade. RIPK1/RIPK3 forms a complex with JAK1 to promote STAT1 activation in IECs. The RIPK1/RIPK3-mediated inflammatory cascade of alloreactive T-cell responses results in intestinal tissue damage, converting the local inflammation into a systemic syndrome. Human patients with severe GVHD showed highly activated RIPK1 in the colon epithelium. Finally, we discover a selective and potent RIPK1 inhibitor (Zharp1-211) that significantly reduces JAK/STAT1-mediated expression of chemokines and MHC class II molecules in IECs, restores intestinal homeostasis, and arrests GVHD without compromising the graft-versus-leukemia (GVL) effect. Thus, targeting RIPK1/RIPK3 in IECs represents an effective nonimmunosuppressive strategy for GVHD treatment and potentially for other diseases involving GI tract inflammation.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.2022017262
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2023
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
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    Online Resource
  • 4
    Online Resource
    Online Resource
    Microarray Analysis of the Peripheral Monocytes From Waldenstrom's Macroglobulinemia Patients Reveals a Distinct Gene Expression Profile
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 2010-2010
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 2010-2010
    Abstract: Abstract 2010 Background: Waldenstrom's macroglobulinemia (WM) is a B-cell malignancy characterized by the accumulation, predominantly in the bone marrow, of clonally related IgM-secreting lymphoplasmacytic cells. Macrophage derived inflammatory factors are elevated in WM suggesting a possible contribution by monocytes to the growth and survival of WM cells. Patients and Method: Monocytes (CD14+) from the peripheral blood of 8 untreated WM patients, and 6 healthy donors (HDs) were isolated by immunomagnetic bead sorting. Gene expression profiling was then performed using Human Genome U133 Plus 2.0 chips, and data obtained from microarray was analyzed by dChip software with fold change 〉 =2 and p 〈 =0.05 as cut off points. Validation was performed by real time PCR. Results: Using Panther classification, 284 transcripts were identified as significantly different in monocytes derived from WM patients versus HDs. The resulted transcripts are involved in many critical signaling pathways, such as Toll-like immune receptor pathway (i.e. TLR1, TLR4, TLR8, TICAM); inflammatory response (i.e. CD40, PTAFR, FPR2), integrin binding (i.e. RAC2, ILK), chemokinesis (i.e. CCR2, CX3CR1), apoptosis (i.e. TNFSF10), p53 signaling (i.e. GADD45A, 1433F) and G-protein coupled receptors (i.e. CX3CR1). Fifteen of 21 genes were validated by real-time PCR, and were over-expressed in peripheral blood monocytes from WM patients in comparison to healthy age matched donors: Conclusion: Peripheral monocytes from WM patients demonstrate a distinct gene expression profile characterized by up-regulation of genes affecting Toll-like innate immunity, inflammation, and apoptosis. These studies define a distinct microenvironmental signature, and provide a framework for the exploration of novel targets for prognosis and therapy in WM. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.2010.2010
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
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    Online Resource
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