IRF-4 Functions as a Myeloid Tumor Suppressor.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2206-2206
Author(s):  
Jaime Acquaviva ◽  
Jonathan Schatz ◽  
Harinder Singh ◽  
Ruibao Ren
Keyword(s):  
Tumor Suppressor ◽  
Progenitor Cells ◽  
Murine Model ◽  
Cell System ◽  
Myelogenous Leukemia ◽  
Myeloproliferative Disease ◽  
Granulocytic Differentiation ◽  
Gm Csf ◽  
Myeloid Progenitor Cells ◽  
Colony Forming Capacity

Abstract Interferon regulatory factor 4 (IRF-4, also know as pip, LSIRF, ICSAT and MUM1) is a transcription factor with well-characterized functions in B and T cell development and immune response regulation. Though its expression has been demonstrated in macrophages, its function in the myeloid system is not as well characterized. The closely related IRF family member IRF-8 (ICSBP) has more clearly defined functions in the myeloid system. IRF-8 is a critical regulator of myelopoiesis, and its loss has been implicated in the pathogenesis of chronic myelogenous leukemia (CML). IRF-8 deficient mice manifest a CML-like syndrome, and we have shown previously that forced expression of IRF-8 in a BCR/ABL-induced murine model of CML represses the resulting myeloproliferative disease and prolongs survival. In the B-cell system, we have found that IRF-4 and IRF-8 function redundantly at the pre-B-to-B transition point of development. In this study we investigate whether IRF-4 and IRF-8 may also have overlapping function in myeloid cells. Our results show that mice deficient in both IRF-4 and IRF-8 develop from a very early age a more aggressive CML-like disease than mice deficient in IRF-8 alone. Bone marrow progenitors from IRF-4/8 DKO mice have increased proliferation, GM-CSF stimulated granulocytic differentiation, and colony-forming capacity compared to progenitors from WT or single KO mice. These data suggest that IRF-4 plays a role in myeloid lineage development and may act to suppress proliferation and granulocytic differentiation of myeloid progenitor cells. We further examined if, like IRF-8, IRF-4 is able to suppress BCR/ABL mediated transformation. We used a murine stem cell virus vector to co-express BCR/ABL and either IRF-4 or IRF-8 in BM progenitor cells and assessed colony forming capacity of infected cultures as well as the ability of IRF-4 to suppress BCR/ABL induced CML-like disease in a murine model. Our results demonstrate that IRF-4 potently suppresses BCR/ABL induced colony formation and that forced expression of IRF-4 suppresses BCR/ABL-induced CML-like disease in mice even more potently than IRF-8. These results provide direct evidence that IRF-4 is an important myeloid tumor suppressor and may allow elucidation of new molecular pathways significant to the pathogenesis of human CML.

scholarly journals Granulocytic differentiation of myeloid progenitor cells by p130, the retinoblastoma tumor suppressor homologue

Oncogene ◽  
1999 ◽  
Vol 18 (46) ◽  
pp. 6209-6221 ◽  
Author(s):  
Akio Mori ◽  
Hideaki Higashi ◽  
Yutaka Hoshikawa ◽  
Masahiro Imamura ◽  
Masahiro Asaka ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Progenitor Cells ◽  
Granulocytic Differentiation ◽  
Retinoblastoma Tumor Suppressor ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells ◽  
Retinoblastoma Tumor

scholarly journals Expression of Interferon Consensus Sequence Binding Protein (ICSBP) Is Downregulated in Bcr-Abl-Induced Murine Chronic Myelogenous Leukemia-Like Disease, and Forced Coexpression of ICSBP Inhibits Bcr-Abl-Induced Myeloproliferative Disorder

2000 ◽  
Vol 20 (4) ◽  
pp. 1149-1161 ◽  
Author(s):  
Sheryl X. Hao ◽  
Ruibao Ren
Keyword(s):  
Tumor Suppressor ◽  
Chronic Myelogenous Leukemia ◽  
Murine Model ◽  
Binding Protein ◽  
Consensus Sequence ◽  
Chronic Phase ◽  
Myeloproliferative Disorder ◽  
Myelogenous Leukemia ◽  
Myeloproliferative Disease ◽  
Hematopoietic Stem

ABSTRACT Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder resulting from the neoplastic transformation of a hematopoietic stem cell. The majority of cases of CML are associated with the (9;22) chromosome translocation that generates thebcr-abl chimeric gene. Alpha interferon (IFN-α) treatment induces hematological remission and prolongs life in 75% of CML patients in the chronic phase. It has been shown that mice deficient in interferon consensus sequence binding protein (ICSBP), a member of the interferon regulatory factor family, manifest a CML-like syndrome. We have shown that expression of Bcr-Abl in bone marrow (BM) cells from 5-fluorouracil (5-FU)-treated mice by retroviral transduction efficiently induces a myeloproliferative disease in mice resembling human CML. To directly test whether icsbp can function as a tumor suppressor gene, we examined the effect of ICSBP on Bcr-Abl-induced CML-like disease using this murine model for CML. We found that expression of the ICSBP protein was significantly decreased in Bcr-Abl-induced CML-like disease. Forced coexpression of ICSBP inhibited the Bcr-Abl-induced colony formation of BM cells from 5-FU-treated mice in vitro and Bcr-Abl-induced CML-like disease in vivo. Interestingly, coexpression of ICSBP and Bcr-Abl induced a transient B-lymphoproliferative disorder in the murine model of Bcr-Abl-induced CML-like disease. Overexpression of ICSBP consistently promotes rather than inhibits Bcr-Abl-induced B lymphoproliferation in a murine model where BM cells from non-5-FU-treated donors were used, indicating that ICSBP has a specific antitumor activity toward myeloid neoplasms. We also found that overexpression of ICSBP negatively regulated normal hematopoiesis. These data provide direct evidence that ICSBP can act as a tumor suppressor that regulates normal and neoplastic proliferation of hematopoietic cells.

scholarly journals Isolation of myeloid progenitor cells from peripheral blood of chronic myelogenous leukemia patients

Blood ◽  
1982 ◽  
Vol 60 (1) ◽  
pp. 30-37 ◽  
Author(s):  
JD Griffin ◽  
RP Beveridge ◽  
SF Schlossman
Keyword(s):  
Monoclonal Antibodies ◽  
Progenitor Cells ◽  
Chronic Myelogenous Leukemia ◽  
Peripheral Blood ◽  
Myelogenous Leukemia ◽  
Cell Fraction ◽  
Semisolid Medium ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells ◽  
Unique Method

Abstract Myeloid progenitor cells (colony- and cluster-forming cells in semisolid medium, CFU-GM) were purified from the peripheral blood of chronic myelogenous leukemia (CML) patients. Lymphocytes, monocytes, and most immature myeloid cells were simultaneously depleted with specific monoclonal antibodies using an erythrocyte rosette technique for cell separation. Cells expressing Ia-like antigen were then selected from the residual cell population. Day 7 CFU-GM were enriched 44--116-fold in the IA+ cell fraction, when compared to the unseparated cells, and up to 47% of the cells could form a myeloid colony or cluster in culture. This cell fraction contained up to 92% undifferentiated blasts, with the remainder mostly promyelocytes. The enriched CFU-GM cells were dependent on an exogenous supply of colony- stimulating factor for growth, and colony formation was linear with cell concentration over a large range (10(4)-10(1) cells/ml). This technique of rosette depletion and enrichment with specific monoclonal antibodies provides a unique method for purifying a homogenous population of myeloid precursor cells with defined surface antigen characteristics.

scholarly journals Involvement of p21cip-1 and p27kip-1 in the molecular mechanisms of steel factor-induced proliferative synergy in vitro and of p21cip-1 in the maintenance of stem/progenitor cells in vivo

Blood ◽  
1996 ◽  
Vol 88 (10) ◽  
pp. 3710-3719 ◽  
Author(s):  
C Mantel ◽  
Z Luo ◽  
J Canfield ◽  
S Braun ◽  
C Deng ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Proliferative Response ◽  
Myeloid Cell ◽  
Cyclin Dependent Kinase ◽  
Hematopoietic Progenitor ◽  
Gm Csf ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells

Steel factor (SLF) is a hematopoietic cytokine that synergizes with other growth factors to induce a greatly enhanced proliferative state of hematopoietic progenitor cells and factor-dependent cell lines. Even though the in vivo importance of SLF in the maintenance and responsiveness of stem and progenitor cells is well documented, the molecular mechanism involved in its synergistic effects are mainly unknown. Some factor-dependent myeloid cell lines respond to the synergistic proliferative effects of SLF plus other cytokines in a manner similar to that of normal myeloid progenitor cells from bone marrow and cord blood. We show here that SLF can synergize with granulocyte-macrophage colony-stimulating factor (GM-CSF) to induce an enhanced phosphorylation of the retinoblastoma gene product and a synergistic increase in the total intracellular protein level of the cyclin-dependent kinase inhibitor, p21cip-1, which is correlated with a simultaneous decrease in p27kip-1 in the human factor-dependent myeloid cell line, M07e. Moreover, these cytokines synergize to increase p21cip- 1 binding and decrease p27kip-1 binding to cyclin-dependent kinase-2 (cdk2), an enzyme required for normal cell cycle progression; these inverse events correlated with increased cdk2 kinase activity. It is also shown that exogenous purified p21cip-1 can displace p27kip-1 already bound to cdk2 in vitro. These data implicate increased p21cip-1 and decreased p27kip-1 intracellular concentrations and their stoichiometric interplay in the enhanced proliferative status of cells stimulated by the combination of SLF and GM-CSF. In support of these findings, it is shown that hematopoietic progenitor cells from mice lacking p21cip-1 are defective in SLF synergistic proliferative response in vitro. Moreover, the cycling status of marrow and spleen progenitors and absolute numbers of marrow progenitors were significantly decreased in the p21cip-1 -/-, compared with the +/+ mice. We conclude that the cdk threshold regulators p21cip-1 and p27kip- 1 play a critical role in the normal mitogenic response of M07e cells and murine myeloid progenitor cells to these cytokines and particularly in the SLF synergistic proliferative response that is important to the normal maintenance of the stem/progenitor cell compartment.

Diversity and Molecular Modeling of Neutrophil Elastase Mutations in Patients with Severe Congenital Neutropenia and Acute Myelogenous Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1454-1454
Author(s):  
Andrew A.G. Aprikyan ◽  
Steve Stein ◽  
Nara A. Markosyan ◽  
Maxim Totrov ◽  
Ruben Abagyan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Neutrophil Elastase ◽  
Apoptotic Cell ◽  
Myelogenous Leukemia ◽  
Congenital Neutropenia ◽  
Deletion Mutations ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells ◽  
Acute Myelogenous

Abstract Severe congenital neutropenia (SCN) is an inheritable hematopoietic disorder that is characterized by extremely low levels of neutrophils in peripheral circulation and maturation arrest of bone marrow myeloid progenitor cells at the promyelocytic stage of differentiation. SCN patients have recurring severe infections and approximately 10% of these patients evolve to develop acute myelogenous leukemia. Recently we reported that an impaired cell survival and cell cycle arrest of bone marrow myeloid progenitor cells was observed in SCN patients compared with controls. We also reported various heterozygous mutations in the neutrophil elastase (NE) gene encoding a serine protease in approximately 80% of SCN patients. We hypothesized that mutations in the NE gene trigger apoptotic cell death of myeloid progenitor cells and subsequent severe neutropenia. Mutational analysis of 15 families with one or more affected family members revealed that mutant NE was present only in affected but not in healthy members of these families suggesting the causative role for mutant NE in pathogenesis of SCN. Sequencing analysis revealed that none of SCN patients negative for NE mutations examined had mutations in the Gfi-1 or WAS gene. Sequencing DNA samples of SCN and SCN/AML patients revealed 40 mutations that are distributed primarily throughout the exons 2 through 5 of the NE gene and result in substitution, deletion, insertion, or truncation mutations. Molecular modeling of the tertiary structure of NE revealed that all these mutations can be grouped into three major categories. The first category includes 19 substitution and insertion mutations that are grouped around the N-glycosylation sites of the neutrophil elastase and may lead to abnormal targeting and subcellular localization of the mutant protease. The second group includes 9 substitution and deletion mutations that alter the side loop of the NE that is necessary for proper oligomerization of neutrophil elastase. The third category includes 12 substitution, truncation, and deletion mutations that either alter or completely eliminate the carboxy-terminus of the mutant protein leading to conformational changes of the binding pocket of the NE, and subsequently to altered substrate specificity and/or an acquired resistance to elastase inhibitors. SCN patients that evolved to develop AML had either substitution, deletion, or truncation mutations from each of the three categories described above. Most mutations are clearly non-conservative, have destabilizing effect on oligomeric structure of mutant protein, and alter dramatically the affinity of mutant NE to various factors participating in its processing and intracellular transport. Flow cytometry analysis of annexin V-labeled cells revealed that expression of representative mutant but not normal NE from each of the three categories of NE mutations in human promyelocytic HL-60 cells triggered apoptotic cell death similar to that observed in bone marrow progenitor cells in SCN patients. These data indicate that impaired cell survival and block of differentiation in SCN is due to heterozygous mutations in the neutrophil elastase gene. Current studies focused on design and screen of specific protease inhibitors capable of blocking the pro-apoptotic effect of mutant neutrophil elastase.

scholarly journals Notch1 and Notch2 Inhibit Myeloid Differentiation in Response to Different Cytokines

1998 ◽  
Vol 18 (4) ◽  
pp. 2324-2333 ◽  
Author(s):  
Anna Bigas ◽  
David I. K. Martin ◽  
Laurie A. Milner
Keyword(s):  
Cytokine Response ◽  
Response Patterns ◽  
Colony Stimulating Factor ◽  
Granulocytic Differentiation ◽  
Gm Csf ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

ABSTRACT We have compared the ability of two mammalian Notch homologs, mouse Notch1 and Notch2, to inhibit the granulocytic differentiation of 32D myeloid progenitor cells. 32D cells undergo granulocytic differentiation when stimulated with either granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF). Expression of the activated intracellular domain of Notch1 inhibits the differentiation induced by G-CSF but not by GM-CSF; conversely, the corresponding domain of Notch2 inhibits differentiation in response to GM-CSF but not to G-CSF. The region immediately C-terminal to the cdc10 domain of Notch confers cytokine specificity on the cdc10 domain. The cytokine response patterns of Notch1 and Notch2 are transferred with this region, which we have termed the Notch cytokine response (NCR) region. The NCR region is also associated with differences in posttranslational modification and subcellular localization of the different Notch molecules. These findings suggest that the multiple forms of Notch found in mammals have structural differences that allow their function to be modulated by specific differentiation signals.

IFN-α promotes the rapid differentiation of monocytes from patients with chronic myeloid leukemia into activated dendritic cells tuned to undergo full maturation after LPS treatment

Blood ◽  
2004 ◽  
Vol 103 (3) ◽  
pp. 980-987 ◽  
Author(s):  
Lucia Gabriele ◽  
Paola Borghi ◽  
Carmela Rozera ◽  
Paola Sestili ◽  
Mauro Andreotti ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cd8 T Cells ◽  
Myelogenous Leukemia ◽  
Interferon Α ◽  
Myeloproliferative Disease ◽  
Gm Csf ◽  
Highly Active ◽  
Rapid Generation ◽  
Lps Treatment

AbstractChronic myelogenous leukemia (CML) is a malignant myeloproliferative disease arising from the clonal expansion of a stem cell expressing the bcr/abl oncogene. CML patients frequently respond to treatment with interferon-α (IFN-α), even though the mechanisms of the response remain unclear. In the present study, we evaluated the role of IFN-α in differentiation and activity of monocyte-derived dendritic cells (DCs) from CML patients as well as in modulation of the cell response to lipopolysaccharide (LPS). Treatment of CML monocytes with IFN-α and granulocyte-macrophage colony-stimulating factor (GM-CSF) resulted in the rapid generation of activated DCs (CML-IFN-DCs) expressing interleukin-15 (IL-15) and the antiapoptotic bcl-2 gene. These cells were fully competent to induce IFN-γ production by cocultured autologous T lymphocytes and expansion of CD8+ T cells. LPS treatment of CML-IFN-DCs, but not of immature DCs generated in the presence of IL-4/GM-CSF, induced the generation of CD8+ T cells reactive against autologous leukemic CD34+ cells. Altogether, these results suggest that (1) the generation of highly active monocyte-derived DCs could be important for the induction of an antitumor response in IFN-treated CML patients and (2) IFN-α can represent a valuable cytokine for the rapid generation of active monocyte-derived DCs to be utilized for vaccination strategies of CML patients. (Blood. 2004;103:980-987)

The combined effects of Il-3, GM-CSF and G-CSF on the in vitro growth of myelodysplastic myeloid progenitor cells

1990 ◽  
Vol 14 (11-12) ◽  
pp. 1019-1025 ◽  
Author(s):  
Martin R. Schipperus ◽  
Pieter Sonneveld ◽  
Jan Lindemans ◽  
Nel Vink ◽  
Margreet Vlastuin ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Combined Effects ◽  
In Vitro Growth ◽  
Gm Csf ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells

scholarly journals Hypermethylation of the 5' region of the calcitonin gene is a property of human lymphoid and acute myeloid malignancies

Blood ◽  
1987 ◽  
Vol 70 (2) ◽  
pp. 412-417 ◽  
Author(s):  
SB Baylin ◽  
ER Fearon ◽  
B Vogelstein ◽  
A de Bustros ◽  
SJ Sharkis ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Progenitor Cells ◽  
Cell Transformation ◽  
Lymphoid Hyperplasia ◽  
Myelogenous Leukemia ◽  
Human Calcitonin ◽  
Barr Virus ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells ◽  
Epstein Barr

An abnormal increase in numbers of CCGG sites methylated in the 5′ region of the human calcitonin (CT) gene occurred in tumor cell DNA samples from 90% (17 of 19) of patients with non-Hodgkin's T and B cell lymphoid neoplasms and in 95% (21 of 22) of tumor cell DNA samples from patients with acute nonlymphocytic leukemia (ANLL). The changes were not seen in patients with chronic myelogenous leukemia (0 of 9). The abnormal methylation patterns appear to be a property only of transformed or malignant cells since they were not found in DNA from nonneoplastic adult tissues including sperm, early myeloid progenitor cells, benign lymphoid hyperplasia, peripheral lymphocytes stimulated to divide, or early myeloid progenitor cells (obtained by immunoaffinity using anti-My-10 antibody), but they did appear after Epstein-Barr virus transformation of lymphocytes. Moreover, during the course of therapy in patients with ANLL, the hypermethylation pattern reflects the presence of the leukemic clone even in normal-appearing granulocytes derived from this clone. The increased methylation of the CT gene may then provide an important molecular marker for biologic events in human cell transformation or tumor progression and may prove clinically useful in monitoring patients with lymphoid and acute myelogenous neoplasms.

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