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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute promyelocytic leukemia (APL) is characterized by the expansion of malignant myeloid cells blocked at the promyelocytic stage of hemopoietic development and is invariably associated with reciprocal chromosomal translocations involving the retinoic acid receptor alpha (RARalpha) gene on chromosome 17. RARalpha variably fuses to PML, PLZF, NPM, NuMA, and Stat5B genes (X genes/proteins). These translocations are balanced and reciprocal, thus leading to the generation of X-RARalpha and RARalpha-X fusion genes of which the products coexist in the APL blast. The invariable involvement in these translocations of RARalpha, a prototypical transcription factor, makes APL a compelling example of aberrant transcriptional mechanisms in the etiopathogenesis of cancer. This paper focuses on the recent progress in defining the molecular mechanisms underlying APL pathogenesis and addresses how this new understanding has allowed the proposal and development of novel therapeutic strategies with compounds such as histone deacetylase inhibitors and inorganic arsenicals such as As2O3 which are currently being tested in murine leukemia models as well as in human APL patients. In particular, the crucial role played by the aberrant transcriptional activities of X-RARalpha and RARalpha-X fusion proteins in APL pathogenesis is discussed by reviewing the relevant therapeutic implications resulting from this analysis.
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PMID:Histone deacetylases and transcriptional therapy with their inhibitors. 1158 60

Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with regard to its clinical course. The limitations of the methods currently available for prognostic assessment in CLL do not allow accurate prediction of the risk of disease progression in individual patients. The recently developed cDNA array technique provides a unique opportunity to study gene expression in various malignancies. To identify new molecular markers for prognostication of CLL patients, we analyzed cDNA arrays by using hierarchical clustering and standard statistic t-test on 34 CLL patients. We found significant expression differences in 78 genes compared to the reference tonsillar B lymphocytes. A cluster of genes, LCP1, PARP, BLR1, DEK, NPM, MCL1, SLP76, STAM, HIVEP1, EVI2B, CD25, HTLF, HIVEP2, BCL2, MNDA, PBX3, EB12, TCF1, CGRP, CD14, ILB, GZMK, GPR17 and CD79B, was associated (P < 0.05) with the unfavorable 11q deletion and also with the unfavorable Binet stages B and C. We present here gene expression profiling that is associated with CLL patients with the 11q23 deletion. Many of the genes in the cluster have not previously been shown to be related to the initiation or progression of CLL. These novel findings provide fundamental information for further attempts to understand the interaction of the clustered genes in the leukomogenesis of CLL in order to better design treatments aimed at specific molecular target(s).
Leukemia 2001 Nov
PMID:Distinct gene expression profiling in chronic lymphocytic leukemia with 11q23 deletion. 1168 13

In peripheral blood of at least 50% of healthy individuals, the translocations t(9;22) BCR/ABL, t(14;18) IgH/BCL-2, t(2;5) NPM-ALK and MLL duplications, which characterize chronic myelogenous leukemia and acute lymphoblastic leukemia, follicular lymphoma, anaplastic large cell lymphoma, and acute myelogenous leukemia, respectively, are detectable by sensitive polymerase chain reaction (PCR). No structural differences between these aberrations in normal or disturbed hematopoiesis are apparent. While the total count of t(9;22)- and t(14;18)-positive cells does not exceed 10(4), those with MLL duplications are more frequent and account for approximately 10(7) cells in the total blood pool. t(14;18)-positive cells seem to be immortalized, but the biological consequences of the other aberrations in positive healthy persons have not been studied in detail. Due to the high frequency of positive individuals, most of them will not suffer from the correspondent leukemia or lymphoma, and criteria for subgroups that may be at a higher risk remain to be determined. Most likely, the number of genetic aberrations in healthy individuals, which so far are only associated with hematopoietic disorders, will increase in the near future.
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PMID:Leukemia- and lymphoma-associated genetic aberrations in healthy individuals. 1190 85

Chromosomal translocations are frequently involved in the pathogenesis of leukemias, lymphomas and sarcomas. They can lead to aberrant expression of oncogenes or the generation of chimeric proteins. Classically, one of the products is thought to be oncogenic. For example, in acute promyelocytic leukaemia (APL), reciprocal chromosomal translocations involving the retinoic acid receptor alpha (RARalpha) gene lead to the formation of two fusion genes: X-RARalpha and RARalpha-X (where X is the alternative RARalpha fusion partner: PML, PLZF, NPM, NuMA and STAT 5b). The X-RARalpha fusion protein is indeed oncogenic. However, recent data indicate that the RARalpha-X product is also critical in determining the biological features of this leukemia. Here, we review the current knowledge on the role of reciprocal products in cancer pathogenesis, and highlight how their expression might impact on the biology of their respective tumour types.
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PMID:Reciprocal products of chromosomal translocations in human cancer pathogenesis: key players or innocent bystanders? 1212 26

The t(15;17)(q22;q21) translocation is tightly linked to the APL phenotype, and the resultant PML-RAR fusion can be demonstrated in 98% of APL cases. Rare variant translocations have been reported, the majority of which on detailed analysis represent cryptic PML-RAR fusions. However, a handful of APL cases have been described with different genotypes. These include the t(11;17)(q23;q21) that produces the PLZF-RAR fusion, t(5;17)(q35;q21) that forms NPM-RAR, t(11;17)(q13;q21) that generates NUMA-RAR, and der(17) that creates STAT5b-RAR. In this review we will discuss these variant translocations, and discuss the insights that we have gained from their study.
Leukemia 2002 Oct
PMID:Variations on a theme: the alternate translocations in APL. 1235 44

Acute promyelocytic leukemia (APL) is characterized by a number of features that underpin the need for rapid and accurate diagnosis and demand a highly specific treatment approach. These include the potentially devastating coagulopathy, sensitivity to anthracycline-based chemotherapy regimens, as well as unique responses to all-trans retinoic acid and arsenic trioxide that have revolutionized therapy over the last decade. The chromosomal translocation t(15;17) which generates the PML-RARalpha fusion gene has long been considered the diagnostic hallmark of APL; however, this abnormality is not detected in approximately 10% cases with successful karyotype analysis. In the majority of these cases, the PML-RARalpha fusion gene is still formed, resulting from insertion events or more complex rearrangements. These cases share the beneficial response to retinoids and favorable prognosis of those with documented t(15;17), underscoring the clinical relevance of molecular analyses in diagnostic refinement. In other cases of t(15;17) negative APL, various chromosomal rearrangements involving 17q21 have been documented leading to fusion of RARalpha to alternative partners, namely PLZF, NPM, NuMA and STAT5b. The nature of the fusion partner has a significant bearing upon disease characteristics, including sensitivity to retinoids and arsenic trioxide. APL has provided an exciting treatment model for other forms of AML whereby therapeutic approach is directed towards cytogenetically and molecularly defined subgroups and further modified according to response as determined by minimal residual disease (MRD) monitoring. Recent studies suggest that rigorous MRD monitoring, coupled with pre-emptive therapy at the point of molecular relapse improves survival in the relatively small subgroup of PML-RARalpha positive patients with 'poor risk' disease. Advent of 'real-time' quantitative RT-PCR technology seems set to yield further improvements in the predictive value of MRD assessment, achieve more rapid sample throughput and facilitate inter- and intra-laboratory standardization, thereby enabling more reliable comparison of data between international trial groups.
Leukemia 2002 Oct
PMID:Acute promyelocytic leukemia: a model for the role of molecular diagnosis and residual disease monitoring in directing treatment approach in acute myeloid leukemia. 1235 47

Acute promyelocytic leukaemia (APL) is characterised by chromosomal rearrangements of 17q21, leading to fusion of the gene encoding retinoic acid receptor alpha (RARalpha) to a number of alternative partner genes (X), the most frequent of which are PML (>95%), PLZF (0.8%) and NPM (0.5%). Over the last few years, it has been established that the X-RARalpha fusion proteins play a key role in the pathogenesis of APL through recruitment of co-repressors and the histone deacetylase (HDAC)-complex to repress genes implicated in myeloid differentiation. Paradoxically, the X-RARalpha fusion protein has the potential to mediate myeloid differentiation at pharmacological doses of its ligand (all trans-retinoic acid (ATRA)), which is dependent on the dissociation of the HDAC/co-repressor complex. Arsenic compounds have also been shown to be promising therapeutic agents, leading to differentiation and apoptosis of APL blasts. It is now apparent that the nature of the RARalpha-fusion partner is a critical determinant of response to ATRA and arsenic, underlining the importance of cytogenetic and molecular characterisation of patients with suspected APL to determine the most appropriate treatment approach. Standard protocols involving ATRA combined with anthracycline-based chemotherapy, lead to cure of approximately 70% patients with PML-RARalpha-associated APL. Patients at high risk of relapse can be identified by minimal residual disease monitoring. The challenge for future studies is to improve complete remission rates through reduction of induction deaths, particularly due to haemorrhage, identification of patients at high risk of relapse who would benefit from additional therapy, and identification of a favourable-risk group, for which treatment intensity could be reduced, thereby reducing risks of treatment toxicity and development of secondary leukaemia/myelodysplasia. With the advent of ATRA and arsenic, APL has already provided the first example of successful molecularly targeted therapy; it is hoped that with further understanding of the pathogenesis of the disease, the next decade will yield further improvements in the outlook for these patients.
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PMID:The molecular pathogenesis of acute promyelocytic leukaemia: implications for the clinical management of the disease. 1264 21

We have investigated the effects of acute promyelocytic leukemia (APL) fusion gene NPM-RARalpha on the function of PPARgamma using the monoblastic cell line U937. U937 cells were transduced using a retrovirus carrying NPM-RARalpha. While treatment with the synthetic PPARgamma ligand troglitazone (TG) had no effect on the viability of U937 cells, TG treatment of U937/NPM-RARalpha cells resulted in a dramatic decrease in cell viability, dependent upon both the concentration of TG and the level of expression of NPM-RARalpha. Analysis of the cell cycle profile and flow cytometry with annexin V confirmed that these effects of TG were due to induction of apoptosis. Induction of apoptosis was accompanied by caspase-8 and caspase-9 activation, and could be blocked by treatment with the caspase inhibitor Z-VAD-FMK. Cotreatment of U937/NPM-RARalpha cells with all-trans retinoic acid (atRA) abrogated the induction of apoptosis by TG. Induction of apoptosis was seen also in the PML-RARalpha-expressing APL cell line NB4, and in several other atRA-sensitive leukemia cell lines, demonstrating that this effect is limited neither to the monocyte lineage nor to the rare NPM-RARalpha fusion variant. RXRalpha/NPM-RARalpha heterodimers were found to interact directly with a PPARgamma-responsive element in vitro. We conclude that in the presence of X-RARalpha, TG induces cell death due to apoptosis via the caspase pathway. These observations suggest the investigation of PPARgamma ligands as therapeutic agents in acute leukemia.
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PMID:Expression of NPM-RARalpha fusion gene in hematopoietic cells confers sensitivity to troglitazone-induced apoptosis. 1450 22

Human myelogenous leukaemia K562 cells were induced to undergo megakaryocytic differentiation by treatment with phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) (20 nM, 24-72 h). The steady-state level of nucleophosmin/B23 mRNA decreased during the TPA-induced differentiation. There was also decrease in the level of cellular nucleophosmin/B23 protein and appearance of its degraded product (25 kDa) during the TPA-induced differentiation. Furthermore, K562/B23 (wild type), K562/D1 (delta280-294) and K562/D2 (delta263-294) cells were less, while K562/D3 (delta244-294) cells were more responsive to TPA-induced differentiation as compared to K562/vector or parental K562 cells. Activation of the ERK/MAPK was observed in parental K562 cells upon TPA treatment (5 nM, 5-30 min). As compared to K562/vector cells, less activation of ERK/MAPK was observed in K562/D2 cells, while ERK/MAPK was highly activated in K562/D3 cells upon TPA treatment. Our results indicate that nucleophosmin/B23 plays an important role in TPA-induced differentiation of K562 cells and the amino acids 244-294 at C-terminal of nucleophosmin/B23 could be an important site for regulation of cellular response to differentiation.
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PMID:Involvement of nucleophosmin/B23 in TPA-induced megakaryocytic differentiation of K562 cells. 1452 Apr 67

The retinoic acid-induced differentiation of human leukemia HL-60 cells towards mature granulocytic cells was accompanied by the decline in the protein levels of c-myc, nucleophosmin/B23 and its promoter activity. These RA-induced effects were further enhanced by the concurrent treatment of HL-60 cells with p38 map kinase inhibitor SB203580 (SB). It seems that there is a strong correlation of nucleophosmin/B23 and c-Myc expressions in cells under RA treatment. Furthermore, nucleophosmin/B23 promoter activity decreased upon c-Myc antisense-mediated reduction of intracellular amount of c-Myc. CHIP assays showed that binding of c-Myc to the nucleophosmin/B23 promoter decreased in RA-treated cells. Thus, nucleophosmin/B23 expression is targeted by c-Myc during RA-induced differentiation. These results provide evidence for a novel mechanism of transcriptional downregulation of nucleophosmin/B23 and the functional role of c-Myc in RA-induced differentiation.
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PMID:c-Myc-mediated expression of nucleophosmin/B23 decreases during retinoic acid-induced differentiation of human leukemia HL-60 cells. 1558 22


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