Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the clinical response of fludarabine-refractory CLL patients treated with high-dose methylprednisolone (HDMP) and rituximab. Fourteen patients were treated with three cycles of rituximab (375 mg/m(2) weekly for 4 weeks) in combination with HDMP (1 gm/m(2) daily for 5 days). All patients were refractory to fludarabine and 86% had high-risk disease by the modified Rai classification. In all, 79% of the patients had CLL cells that expressed ZAP-70 and three patients had poor prognostic cytogenetics. The overall response rate was 93% and the complete remission rate was 36%. The median time-to-progression was 15 months and the median time-to-next treatment was 22 months. Median survival has not been reached after a median follow up of 40 months. Four patients have died of progressive disease. Patients tolerated the treatment well and serious adverse events were rare. This allowed patients to receive all planned treatments on schedule with no dose modifications. All but one patient responded to treatment and the overall survival and time-to-progression were superior to those of other published salvage regimens.
Leukemia 2008 Nov
PMID:Rituximab in combination with high-dose methylprednisolone for the treatment of fludarabine refractory high-risk chronic lymphocytic leukemia. 1875 25

B cell chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia that follows an extremely variable clinical course. Several important prognostic parameters defining pathogenic and clinical subgroups of CLL have been identified and validated recently. The biological significance of immunoglobulin (Ig) heavy chain variable region gene (IgHV) mutational status and associated ZAP-70 over-expression, CD38 and chromosomal aberrations have enabled to identify patients at high risk for early disease progression and inferior survival. Moreover, studies of the B cell antigen receptor (BCR) structure and receptor signalling have been most helpful in revealing some new aspects of the biology of this disease. In particular, the analysis of IG genes has revealed that the expressed IgHV/IgKV/IgLV gene repertoires of CLL cells differ from those of normal B cells. A further unique feature of the CLL IG repertoire is the existence of subsets of cases with "stereotyped" BCRs. Accumulating molecular and phenotypic data support the notion that CLL development and evolution is not a simple scholastic event and strongly indicates a role for antigen in driving the cell of origin for at least some subsets of CLL cases.
 ...
PMID:Chronic lymphocytic leukaemia: an immunobiology approach. 1879 35

The 8;21 translocation, which involves the gene encoding the RUNX family DNA-binding transcription factor AML1 (RUNX1) on chromosome 21 and the ETO (MTG8) gene on chromosome 8, generates AML1-ETO fusion proteins. Previous analyses have demonstrated that full-length AML1-ETO blocks AML1 function and requires additional mutagenic events to promote leukemia. More recently, we have identified an alternatively spliced form of AML1-ETO, AML1-ETO9a, from t(8;21) acute myeloid leukemia (AML) patient samples. AML1-ETO9a lacks the C-terminal NHR3 and NHR4 domains of AML1-ETO and is highly leukemogenic in the mouse model. Here, we report that the AML1 DNA-binding domain and the ETO NHR2-dimerization domain, but not the ETO NHR1 domain, are critical for the induction of AML by AML1-ETO9a. A region between NHR1 and NHR2 affects latency of leukemogenesis. These results provide valuable insight into further analysis of the molecular mechanism of t(8;21) in leukemogenesis.
 ...
PMID:RUNX1/AML1 DNA-binding domain and ETO/MTG8 NHR2-dimerization domain are critical to AML1-ETO9a leukemogenesis. 1903 4

In lymphatic tissues, chronic lymphocytic leukemia (CLL) cells are interspersed with CD68(+) nurselike cells (NLCs), T cells, and other stromal cells that constitute the leukemia microenvironment. However, the mechanism regulating colocalization of CLL and these accessory cells are largely unknown. To dissect the molecular cross talk between CLL and NLCs, we profiled the gene expression of CD19-purified CLL cells before and after coculture with NLCs. NLC coculture induced high-level expression of B-cell maturation antigen and 2 chemoattractants (CCL3, CCL4) by CLL cells. CCL3/CCL4 induction in NLC cocultures correlated with ZAP-70 expression by CLL cells. High CCL3/CCL4 protein levels were found in CLL cocultures with NLCs, and CCL3/CCL4 induction was abrogated by R406, a Syk inhibitor, suggesting that NLCs induce these chemokines via B-cell receptor (BCR) activation. BCR triggering also caused robust CCL3/CCL4 protein secretion by CLL cells. High CCL3 and CCL4 plasma levels in CLL patients suggest that this pathway plays a role in vivo. These studies reveal a novel mechanism of cross talk between CLL cells and their microenvironment, namely, the secretion of 2 T-cell chemokines in response to NLC coculture and BCR stimulation. Through these chemokines, CLL cells can recruit accessory cells and thereby actively create a supportive microenvironment.
 ...
PMID:High-level expression of the T-cell chemokines CCL3 and CCL4 by chronic lymphocytic leukemia B cells in nurselike cell cocultures and after BCR stimulation. 1907 30

This study was aimed to establish the cell lines of human T-cell leukemia virus type-1 (HTLV-1) tax gene expression and their biological activity. The eukaryotic vector pCMV-tax and pCMV-neo-Bam were transfected into Jurkat E6-1 by using liposome, following screening with G418, the tax gene expression cell line-TaxP and the negative cell lines-TaxN were selected and enriched. Then, the mRNA expressions of LAT, SLP70, ZAP70 and NF-kappaB (p65) were measured by using RT-PCR; the NF-kappaB bioactivity was tested after transfecting the pNF-kappaB-Luc plasmids into TaxP and TaxN cells; meanwhile CD25, CD69 expressions on surface of the two cell lines were tested by flow cytometry. The results showed that TaxP and TaxN cell lines were established and the tax gene expression was detected; as compared with TaxN, the mRNA expressions of LAT, SLP70 and ZAP70 in TaxP were enhanced (p<0.05), while the NF-kappaB bioactivity in TaxP cells was stronger than that in TaxN cells (p<0.01). The CD25, CD69 on TaxP cells surface was highly expressed. It is concluded that TaxP and TaxN cell lines are established, TAX protein could promote the activation of T cells and activate the NF-kappaB pathway.
 ...
PMID:[Establishment of the tax gene expression cell lines and their biological activity]. 1909 58

Zeta-chain-associated protein (ZAP-70) and spleen tyrosine kinase (Syk) are structurally and functionally homologous tyrosine kinases playing a role in the T- and B-cell signal transduction. Their activation can lead to lymphokine production, cytolitic activity, antibody secretion, cell proliferation, differentiation, survival and phagocytosis. Anomalous ZAP-70 and Syk expression is reported to be related to tumor formation and progression, and ZAP-70 immunoreactivity is a good prognostic marker of disease progression in human chronic lymphocytic leukaemia (CLL). Until now, to our knowledge, there are no reports about canine ZAP-70 and Syk expression profiles. In the present study, a RT-PCR procedure for the quali-quantitative evaluation of canine ZAP-70 and Syk transcripts was designed. The expression patterns of canine ZAP-70 and Syk mRNAs were evaluated in canine leukocyte subpopulations and in peripheral whole blood samples from healthy dogs and from dogs with different types of leukaemia. Similarly to humans, normal canine CD4+ and CD8+ T cells showed high expression of ZAP-70, whereas Syk was abundantly expressed in normal CD21+ B cells. The expression profile of ZAP-70 and Syk was markedly different in canine normal and leukaemic blood. Decreased Syk expression was detected in dogs with T-cell CLL, whereas decreased ZAP-70 expression was detected in dogs with B-cell CLL and B-cell acute lymphocytic leukaemia (ALL). The comparison of ZAP-70 and Syk mRNA levels between normal and leukaemic peripheral whole blood showed that the expression ratio ZAP-70/Syk is subjected to modification depending on the leukaemia status of patients. The results of the present work open an interesting topic for leukaemogenesis investigation and are the basis for further studies for a proper evaluation of the potential utility of these parameters for the diagnosis and prognosis of canine T- and B-cell leukaemia.
 ...
PMID:ZAP-70 and Syk expression in canine lymphoid cells and preliminary results on leukaemia cases. 1914 11

Chronic lymphocytic leukemia is an adult-onset leukemia with a heterogeneous clinical behavior. When chronic lymphocytic leukemia cases were divided on the basis of IgV(H) mutational status, widely differing clinical courses were revealed. Since IgV(H) sequencing is difficult to perform in a routine diagnostic laboratory, finding a surrogate for IgV(H) mutational status seems an important priority. In the present study, we proposed the use of Cryptochrome-1 as a new prognostic marker in early-stage chronic lymphocytic leukemia. Seventy patients (Binet stage A, without treatment) were included in the study. We correlated Cryptochrome-1 mRNA with well established prognostic markers such as IgV(H) mutations, ZAP70, LPL or CD38 expression and chromosomal abnormalities. High Cryptochrome-1 expression correlated with IgV(H) unmutated samples. In addition, Cryptochrome-1 was a valuable predictor of disease progression in early-stage chronic lymphocytic leukemia, therefore it can be introduced in clinical practice with the advantage of a simplified method of quantification.
 ...
PMID:Cryptochrome-1 expression: a new prognostic marker in B-cell chronic lymphocytic leukemia. 1918 92

A number of molecular targets have been identified in leukemia, based on the understanding of signaling pathways controlling cell differentiation, proliferation, apoptosis, and malignant transformation. Growth factors and integrins interact with their receptors and activate signaling cascades with intimate interconnections. The specific niches within the bone marrow microenvironment may provide a sanctuary for subpopulations of leukemic cells to escape chemotherapy-induced death and acquire drug resistance. Investigations into bone marrow stroma-leukemia crosstalk may result in the development of strategies against the acquisition of a chemo-resistant phenotype and enhance the efficacy of therapies in leukemia. In recent studies, we proposed novel therapeutic interventions targeting the microenvironment/leukemia interaction focusing on SDF1/CXCR4, ILK/PI3K/Akt, TGF-beta, and Notch signaling. Gene transcriptional activity is regulated by chromatin modification and DNA methylation. Nuclear receptors such as RAR, RXR, and PPARgamma exert histone acetyl transferase activity (HAT). The transcription of target genes is initiated following the ligation of these receptors, recruitment of co-activators, and replacement of repressors. We demonstrated that histone acetylation by the PPARgamma agonist CDDO, RAR/RXR agonist ATRA, and/or histone deacetylase inhibitors (HDACIs) reversed the silenced RARbeta and MDR1 genes in acute promyelocytic leukemia, and that HDACI induced apoptosis with phagocytosis through the induction of Annexin A1 in AML1/ETO-positive acute myelocytic leukemia (AML) cells. The translation of research findings into effective clinical laboratory tests is an important approach. The flow cytometric technique is a powerful tool in the field of clinical laboratory medicine, with its accurate and rapid analysis. We carried out phospho-specific flow cytometry to investigate protein phosphorylation in AML cells and detect ZAP-70 in chronic lymphocytic leukemia cells, including the evaluation of antibodies, staining epitopes, fixing and permeabilizing methods, and analyzing systems. Finally, we emphasize the potential applications of research findings and methods in the fields of clinical medicine, molecular diagnosis, and targeting therapy.
 ...
PMID:[Molecular diagnosis of and molecular targeting therapy for leukemia]. 1931 19

Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia in the Western countries, however, it is infrequent in the Eastern countries. The direct antiglobulin test (DAT) may be positive at some time during the disease course of CLL. The aim of this study was to explore the prognostic impact of positive DAT at diagnosis in Chinese patients with CLL. In 123 Chinese patients with CLL, 34 (27.6%) patients presented with a positive DAT at diagnosis. However only 12 patients (9.8%) with a positive DAT developed autoimmune hemolytic anemia (AHA). According to the correlation analysis, advanced Binet stage (p < 0.001), high level of serum lactate dehydrogenase (LDH) (p = 0.003) and beta(2)-microglobulin (beta(2)-M) (p = 0.011), unmutated immunoglobulin heavy chain variable gene status (p < 0.001), positive ZAP-70 (p = 0.012), and trisomy 12 cytogenetic aberration (p = 0.004) emerged as factors significantly related to the occurrence of DAT-positive. Patients with positive DAT had significantly shorter survival times than patients with negative DAT (p = 0.009). Five-year OS percentages of DAT-positivity and DAT-negative patients were 72.8% and 97.5%, respectively. It was showed that DAT status might be applied for the assessment of prognosis in patients with CLL.
 ...
PMID:The negative prognostic significance of positive direct antiglobulin test in Chinese patients with chronic lymphocytic leukemia. 1960 77

B-cell chronic lymphocytic leukemia (CLL), the most frequent leukemia in the Western world, is characterized by extremely variable clinical courses with survivals ranging from 1 to more than 15 years. The pathogenetic factors playing a key role in defining the biological features of CLL cells, hence eventually influencing the clinical aggressiveness of the disease, are here divided into "intrinsic factors", mainly genomic alterations of CLL cells, and "extrinsic factors", responsible for direct microenvironmental interactions of CLL cells; the latter group includes interactions of CLL cells occurring via the surface B cell receptor (BCR) and dependent to specific molecular features of the BCR itself and/or to the presence of the BCR-associated molecule ZAP-70, or via other non-BCR-dependent interactions, e.g. specific receptor/ligand interactions, such as CD38/CD31 or CD49d/VCAM-1. A putative final model, discussing the pathogenesis and the clinicobiological features of CLL in relationship of these factors, is also provided.
 ...
PMID:Intrinsic and extrinsic factors influencing the clinical course of B-cell chronic lymphocytic leukemia: prognostic markers with pathogenetic relevance. 1971 92


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>