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R J Arceci

Publications and source records attributed to R J Arceci.

At least 19 recordsLinked to original sources
PubMed2006

Biology of Langerhans cells and Langerhans cell histiocytosis.

Langerhans cells (LC) are epidermal dendritic cells (DC). They play an important role in the initiation of immune responses through antigen uptake, processing, and presentation to T cells. Langerhans cell histiocytosis (LCH) is a rare disease in which accumulation of cells with LC characteristics (LCH cells) occur. LCH lesions are further characterized by the presence of other cell types, such as T cells, multinucleated giant cells (MGC), macrophages (MPhi), eosinophils, stromal cells, and natural killer cells (NK cells). Much has been learned about the pathophysiology of LCH by studying properties of these different cells and their interaction with each other through cytokines/chemokines. In this review we discuss the properties and interactions of the different cells involved in LCH pathophysiology with the hope of better understanding this enigmatic disorder.

Animals↗
PubMed2005

Long-term results of children with acute myeloid leukemia: a report of three consecutive Phase III trials by the Children's Cancer Group: CCG 251, CCG 213 and CCG 2891.

The Children's Cancer Group (CCG) conducted three Phase III prospective clinical trials for children with de novo acute myeloid leukemia between the years 1979 and 1995. A total of 1903 eligible children ages birth to 21 years of age were enrolled on CCG 251 (n=485), CCG 213 (n=532) and CCG 2891 (n=886). Follow-up is ongoing, with medians of 7.9, 10.9 and 8.6 years, respectively. These three clinical trials developed dose- and time-intensive induction regimens based upon high-dose cytarabine and daunomycin and randomly assigned patients to allogeneic bone marrow transplantation in first remission if an HLA-matched related donor was identified. Despite dose- and time-intensive induction regimens, remission induction rates remained relatively stable at 77-78%. However, overall survival, event-free survival and disease-free survival (DFS) increased for patients receiving intensive-timing induction therapy in comparison to patients who received standard-timing induction, regardless of the type of postremission therapy. Outcomes were best for patients receiving intensive-timing induction followed by matched related donor allogeneic transplantation with DFS of 65+/-9% at 6 years. These three clinical trials have established a strong foundation for the development of future studies focusing on further risk group stratification and the development of novel, molecularly-targeted therapies.

Acute Disease↗
PubMed2001

STAT3 activation is required for Asp(816) mutant c-Kit induced tumorigenicity.

Activating mutations of c-kit at codon 816 (Asp(816)) have been identified in variety of malignancies, including acute myeloid leukemia (AML), mastocytosis and germ cell tumors. The mutant c-Kit receptor confers cytokine independence and induces tumorigenicity. However, the molecular mechanisms, particularly the changes in the signal transduction pathways, responsible for these biological effects induced by mutant c-Kit are largely undefined. Using the human embryonic kidney cell line, 293, we show in the current report that constitutive activation of STAT3 and STAT1 is associated with D816H mutant c-Kit. Transfection of dominant negative STAT3, but not STAT1 inhibits mutant c-Kit mediated anchorage-independent growth in vitro and tumor formation in vivo. Expression of constitutively activated STAT3 restores the mutant c-Kit receptor's transforming ability in 293 cells. These results demonstrate that activation of STAT3 by Asp(816) mutant c-Kit is required for the anchorage-independent growth and tumorigenicity induced by Asp(816) mutant c-Kit.

Amino Acid Substitution↗
PubMed2001

Signal transducer and activator of transcription 3 activation is required for Asp(816) mutant c-Kit-mediated cytokine-independent survival and proliferation in human leukemia cells.

Activating mutations of c-kit at codon 816 (Asp(816)) have been implicated in a variety of malignancies, including acute myeloid leukemia (AML). The mutant c-Kit receptor confers cytokine-independent survival of leukemia cells and induces tumorigenicity. Changes in the signal transduction pathways responsible for Asp(816) mutant c-Kit-mediated biologic effects are largely undefined. The results of this study show that Asp(816) mutant c-Kit induces constitutive activation of signal transducer and activator of transcription 3 (STAT3) and STAT1, and up-regulates STAT3 downstream targets, Bcl-x(L) and c-myc. The phosphatidylinositol-3-kinase (PI-3K)/Akt pathway, but not the Ras-mediated mitogen-activated protein (MAP) kinase pathway, is also constitutively activated by Asp(816) mutant c-Kit. Suppression of STAT3 activation by a dominant negative molecule in MO7e leukemia cells transduced with mutant c-kit inhibits stem cell factor (SCF)-independent survival and proliferation, accompanied by the down-regulation of Bcl-x(L) and c-myc. However, activated STAT3 does not appear to be the sole mediator that is responsible for the phenotypic changes induced by Asp(816) mutant c-Kit, because expression of constitutively activated STAT3 in MO7e cells does not completely reconstitute cytokine independence. Activation of other signaling components by mutant c-Kit, such as those in the PI-3K/Akt pathway, is demonstrated and may also be needed for the mutant c-Kit-mediated biologic effects. The investigation of altered signal transduction pathways and the resulting functional consequences mediated by Asp(816) mutant c-Kit should provide important information for the characterization of subsets of leukemia and potential molecular pathways for therapeutic targeting. (Blood. 2001;97:3559-3567)

Aspartic Acid↗
PubMed2001

An SNF2 factor involved in mammalian development and cellular proliferation.

Members of the SNF2 (Sucrose Non-Fermenter) family of chromatin-remodeling proteins function in processes ranging from DNA repair to transcription to methylation. Using differential display, we recently identified a novel member of the SNF2 family that is highly expressed at the mRNA level in proliferating cells and is down-regulated during apoptosis. We have named this gene PASG (Proliferation-Associated SNF2-like Gene). Northern blot analysis of adult mouse tissues shows PASG to be highly expressed in proliferating organs such as thymus, bone marrow, and testis and absent from nonproliferative tissues such as brain and heart. In situ hybridization analysis of mouse embryos shows that PASG is differentially expressed during development, with highest expression in developing face, limbs, skeletal muscle, heart, and tail. In vitro, PASG expression correlates with a shift from a quiescent to a proliferative state. Mice null for PASG (also known as LSH or Hells) are reported to die perinatally, although the mechanism for lethality is unclear (Geiman and Muegge, 2000). To test the hypothesis that PASG functions in cell proliferation, we compared 5-bromodeoxyuridine (BrdU) incorporation in C33A cells transiently transfected with PASG versus empty vector and found that PASG transfected cells showed a significant decrease in the amount of BrdU incorporation. These findings suggest that PASG plays a role in cell proliferation and may function in the development of multiple cell lineages during murine embryogenesis.

3T3 Cells↗
PubMed2001

Activating mutations of c-kit at codon 816 confer drug resistance in human leukemia cells.

An improved understanding of how leukemia cells grow and become resistant to treatment remains critical for developing more effective therapies. We have identified activating mutations of c-kit at codon 816 (Asp(816) ) from a revertant of the cytokine-dependent acute myeloid leukemia (AML) cell line, MO7e (D816H), and de novo childhood AML (D816N). Following transduction of the mutant c-kit cDNAs, MO7e cells acquire a growth advantage and resistance to apoptosis in response to chemotherapeutic drugs and ionizing radiation, in addition to cytokine-independent survival. Although stimulation of mutant c-kit-bearing MO7e cells with stem cell factor (SCF), a ligand for c-Kit, does not have a significant effect on cell proliferation, SCF further inhibits apoptosis induced by cytotoxic agents. These results suggest a potentially important role of Asp(816) mutations of c-kit in both malignant cell proliferation and resistance to therapy.

Amino Acid Substitution↗
PubMed2000

Proliferation-associated SNF2-like gene (PASG): a SNF2 family member altered in leukemia.

To identify genes involved in cell growth and/or apoptosis in leukemia, differential display was used to identify mRNAs that showed altered expression levels after cytokine withdrawal from the cytokine-dependent MO7e cell line. Sequence analysis of one transcript that showed a profound decrease in expression after cytokine withdrawal revealed it to be a member of the SNF2 family of chromatin remodeling ATPases. This cDNA had a 2514-nucleotide (838-amino acid) open reading frame and encoded an additional 230 amino acids at the NH2 terminus compared with the murine homologue, lsh, and the human counterpart, Hells. This gene locus has been designated SMARCA6 (SWI/SNF2-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 6). The highest levels of mRNA expression in humans are observed in proliferative tissues such as the thymus, testis, and bone marrow. Whereas cytokine withdrawal in MO7e cells leads to apoptosis and decreased mRNA expression, growth arrest without the induction of apoptosis of MO7e cells also leads to down-regulation of mRNA expression, suggesting an association with cell proliferation and not suppression of apoptosis. Nuclear localization of this SNF2-like putative helicase is dependent on a nuclear localization sequence located in the NH2-terminal region. Based on sequence homology to other SNF2-like helicases, the pattern of tissue expression, and the association of expression with cell proliferation, we refer to the protein product as proliferation-associated SNF2-like gene product [PASG (D. W. Lee et al., Blood, 94: 594a, 1999)]. Examination of acute myelogenous leukemia and acute lymphoblastic leukemia samples revealed a high frequency of a PASG transcript containing an in-frame 75-nucleotide deletion, which codes for a conserved motif known to be critical for the transactivation activity of a related yeast SWI/SNF polypeptide. These results extend our knowledge of this SNF2-like family member and suggest a role for PASG in leukemogenesis.

Alternative Splicing↗
PubMed2000

Therapy for acute myeloid leukemia: intensive timing of induction chemotherapy.

Children's Cancer Group (CCG) study 2891 for children with previously untreated acute myeloid leukemia enrolled more than 1200 patients between 1989 and 1995. This study showed that increased dose intensity during induction therapy improved survival for all patients except those with Down syndrome, where it proved harmful. Although increased dose intensity improved survival, it did not improve remission induction rate, indicating that the quality of remissions varies. This finding complicates the evaluation of postremission therapy options, which CCG 2891 also evaluated. Survival with related-donor allogeneic bone marrow transplantation was superior to survival with both purged autologous bone marrow transplantation and a more standard chemotherapy consolidation, whereas survival for autologous transplantation and chemotherapy was equivalent.

Acute Disease↗
PubMed2000

Mitoxantrone, etoposide, and cyclosporine therapy in pediatric patients with recurrent or refractory acute myeloid leukemia.

PURPOSE: To determine the remission rate and toxicity of mitoxantrone, etoposide, and cyclosporine (MEC) therapy, multidrug resistance-1 (MDR1) status, and steady-state cyclosporine (CSA) levels in children with relapsed and/or refractory acute myeloid leukemia. PATIENTS AND METHODS: MEC therapy consisted of mitoxantrone 6 mg/m(2)/d for 5 days, etoposide 60 mg/m(2)/d for 5 days, and CSA 10 mg/kg for 2 hours followed by 30 mg/kg/d as a continuous infusion for 98 hours. Because of pharmacokinetic interactions, drug doses were decreased to 60% of those found to be effective without coadministration of CSA. MDR1 expression was evaluated by reverse transcriptase polymerase chain reaction, flow cytometry, and the ability of CSA at 2.5 micromol/L to increase intracellular accumulation of (3)H-daunomycin in blasts from bone marrow specimens. RESULTS: The remission rate was 35% (n = 23 of 66). Overall, 35% of patients (n = 23) achieved complete remission (CR), 12% of patients (n = 8) achieved partial remission, and 9% of patients (n = 6) died of infection. Exposure to CSA levels of greater than 2,400 ng/mL was achieved in 95% of patients (n = 56 of 59). Toxicities included infection, cardiotoxicity, myelosuppression, stomatitis, and reversible increases in serum creatinine and bilirubin. In most who had relapsed while receiving therapy or whose induction therapy had failed, response was not significantly different for MDR1-positive and MDR1-negative patients. CONCLUSION: Serum levels of CSA capable of reversing multidrug resistance are achievable in children with acceptable toxicity. The CR rate of 35% achieved in this study is comparable to previously reported results using standard doses of mitoxantrone and etoposide. The use of CSA may have improved the response rate for the MDR1-positive patients so that it was not different from that for the MDR1-negative patients.

Adolescent↗
PubMed1999

Congenital and neonatal leukemia.

Congenital and neonatal leukemia occur rarely, yet carry high mortality rates and pose special problems for the perinatologist and hematologist. Although the etiology is unknown, the presence of leukemia at birth suggests genetic abnormalities and possibly intrauterine exposures to drugs or other toxins as contributing factors. Specific chromosomal rearrangements that are common in congenital leukemia have recently been identified and promise to enhance our understanding of these enigmatic diseases. The differential diagnosis is broad and includes many disorders that occur frequently in the neonatal period. Infants diagnosed with congenital or neonatal leukemia require thorough investigative workup and extensive supportive care. Although the prognosis is poor, recent use of high-intensity multiagent chemotherapy regimens has produced promising results.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Differentiation responses of embryonic endothelium to leukemia inhibitory factor.

The IEM cell line is a murine embryonic endothelial cell line that responds to combinations of basic fibroblast growth factor (bFGF) and leukemia inhibitory factor (LIF) by undergoing proliferation and vasculogenic differentiation in vitro and in vivo. Exposure to LIF and bFGF in vitro permits the IEM cells to specifically chimerize endothelium in vivo and recapitulate normal endothelial development after blastocyst injection. We report here that unmanipulated IEM cells form vascular neoplasias when injected into immunodeficient nude mice. Examination of IEM neoplasia following exposure in vitro to bFGF and LIF before injection into nude mice profoundly reduced or completely suppressed the neoplastic growth of IEM cells. Furthermore, this suppression was observed by treatment with LIF alone, while bFGF treatment did not significantly alter IEM neoplasia and did not modify the LIF-mediated suppression. Characterization of the IEM responses to LIF revealed that the LIF suppression of IEM neoplasia depended on how long the cells were exposed to LIF in vitro. The IEM cell response to LIF was associated with the specific activation of the transcription factor Stat3. Stat1 activation could not be detected in response to LIF, although it is expressed in IEM cells. Our results demonstrate that the LIF-induced differentiation of IEM cells involves suppression of IEM-derived neoplasia and is associated with the specific activation of Stat3.

Acute-Phase Proteins↗
PubMed1998

The potential for antitumor vaccination in acute myelogenous leukemia.

While many advances have been made in the treatment of patients with cancer, significant challenges that remain include tumor cell resistance and the toxicity associated with currently used intensive chemotherapeutic regimens. This is particularly true for patients with acute myelogenous leukemia (AML). Most patients with AML usually are able to achieve complete remission, but only a minority obtain long-term survival. In addition, much of the success achieved has been due to escalation of chemotherapeutic dosing and hematopoietic stem cell transplantation. There is thus a great need for improved therapies which would ideally be able to circumvent drug resistance and more specifically target leukemic cells. Advances in immunobiology over the past century have led to new hope for the development of immune-mediated vaccine therapies for patients with cancer. This review focuses on the development of vaccine approaches for treatment of AML and some of the potential advantages and problems.

Animals↗
PubMed1998

Controversies and new approaches to treatment of Langerhans cell histiocytosis.

There continues to be genuine ambivalence as to whether Langerhans cell histiocytosis (LCH) is a primary neoplastic or immuno-dysregulatory disorder. Treatment strategies have moved from one camp to the other depending upon the most current alleged successes or failures. This has been particularly true for patients who fall outside of the sphere where treatment is minimal or where known treatment approaches are clearly beneficial. However, there is growing evidence that LCH is both the result of clonal proliferation of Langerhans cells and the immunologic consequence of increased cellular activation. This new knowledge should be the basis for the development of new therapeutic approaches for patients with LCH and its complications.

Bone Diseases↗
PubMed1998

Correction of autoimmune lymphoproliferative syndrome by bone marrow transplantation.

This report describes a child with a severe phenotype of autoimmune lymphoproliferative syndrome (ALPS) who developed progressive disease requiring stem cell transplantation. This severe form of ALPS was associated with a novel Fas gene splice site mutation that resulted in functional deletion of exons 8 and 9. While this child shared many clinical features with previously described ALPS cases, including massive lymphadenopathy and circulating alphabeta+ CD3+CD4-CD8-T cells, his disease progressed despite immunosuppressive therapy to a clinically aggressive oligoclonal lymphoproliferation which resembled a diffuse large cell non-Hodgkin's lymphoma. After partial remission was achieved with cytotoxic therapy the patient underwent BMT from an unrelated donor. This is the first reported case of ALPS in which BMT was successfully attempted for correction of a Fas deficiency.

Alternative Splicing↗
PubMed1998

Clinical relevance of transmembrane drug efflux as a mechanism of multidrug resistance.

For cytotoxic agents to have an effect on tumor cells, drugs must first be transported into the cell, potentially be metabolized to an active form, and interact appropriately with target molecules. A final common pathway of cytotoxic agents is usually the initiation of programmed cell death, or apoptosis. Tumor cells overcome the effects of cytotoxic agents at one or more of these levels. The classic multidrug-resistance (MDR) phenotype, as mediated by the drug efflux pump, P-glycoprotein, is one of the most extensively studied mechanisms of drug resistance. Additional drug transporters, such as the multidrug resistance-associated proteins (MRPs), have also been identified and can convey drug-resistance phenotypes. Important questions remain as to how and whether such transport systems can be specifically measured and effectively targeted to improve therapeutic outcomes. Furthermore, alterations in drug targets, drug metabolism, repair of DNA damage caused by drugs, and the inability to initiate programmed cell death can all contribute to drug resistance and must be ultimately considered in the explanation of tumor-cell resistance to therapy. Continued exploration of the pharmacologic methods to circumvent drug resistance, as well as strategies that involve targeted therapy and immunomodulation, should increase the specificity and efficacy of treatments for patients with cancer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗