Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since the translocation breakpoint t(15;17) (q22;q21) in acute promyelocytic leukemia (APL) occurs within the retinoic acid receptor-alpha (RARA) gene, the expression of many genes normally regulated by RARA may be affected by this translocation. To identify genes that may be aberrantly expressed in APL, a subtraction cDNA library of an APL patient with t(15;17) was constructed. A cDNA, pRD1, specifically expressed in APL was identified. DNA sequence analysis of pRD1 showed that this gene is similar to the DNA sequence of annexin VIII, a gene which encodes a vascular anticoagulant. The annexin VIII gene was assigned to chromosome 10, which indicates that specific expression of this gene in APL is not directly involved in the t(15;17) breakpoint region. We have analyzed the expression of annexin VIII gene in nine t(15;17)-positive APL patients and one APL patient with a chromosome 17q-abnormality. We found that all APL samples expressed high levels of the annexin VIII gene. Expression of the annexin VIII gene in all other leukemias, including acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and acute lymphoblastic leukemia, was undetectable, except in one patient with acute myelogenous leukemia in which a very low level of expression was detected. Annexin VIII is highly expressed in the APL cell line, NB4. Its expression was significantly reduced after 8 hours of all-trans retinoic acid (ATRA) treatment, whereas the expression of RARA increased several-fold within 4 hours postinduction. Thus, increased expression of RARA preceded the downregulation of annexin VIII after ATRA induction, suggesting an inverse relationship between RARA and annexin VIII expression. Since increased expression of the fusion transcript was seen after ATRA induction and an APL without a t(15;17) translocation expressed high levels of annexin VIII, it appears that increased expression of annexin VIII in APL is not related to the fusion transcript. Therefore, dysregulation of the RARA gene may be related to the overexpression of annexin VIII in APL.
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PMID:Specific expression of the annexin VIII gene in acute promyelocytic leukemia. 131 14

The capacity to convert exogenous leukotriene A4 to lipoxins (LXs) was investigated in platelet suspensions from patients with myeloproliferative disorders (MPD) (n = 22) and healthy control subjects (n = 14). Platelets isolated from the controls produced mainly LXA4, but also 6(S)-LXA4 and the all-trans isomers of lipoxins A4 and B4, as determined by high-performance liquid chromatography and computerized UV spectroscopy. In comparison to control levels, the mean LX synthesis was significantly lower in platelets from the MPD patients (438.7 +/- 62.8 and 157.4 +/- 31.2 pmol LXA4 per 10(9) platelets, respectively; mean +/- SEM; P = .0001). Platelets from six of the patients showed a particularly low capacity to produce LXs, resulting in LX levels below the detection limit or less than 7% of mean control levels. Notably, all these patients were in blastic crisis of chronic myelogenous leukemia (CML). This severely deficient LX production was paralleled by a dramatically attenuated conversion of arachidonic acid to 12-HETE (12-hydroxyheptadecatrienoic acid), a product formed via the prostaglandin endoperoxide synthase pathway, was normal. In addition, longitudinal studies of CML patients showed that blastic metamorphosis was associated with a markedly reduced capability to synthesize LXs, while this capacity improved after retransformation into a second chronic phase. The results reveal deficient LX synthesis as a novel platelet dysfunction in MPD, particularly in blastic crisis of CML in which an essentially abolished 12-lipoxygenase activity may be a general phenomenon.
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PMID:Deficient lipoxin synthesis: a novel platelet dysfunction in myeloproliferative disorders with special reference to blastic crisis of chronic myelogenous leukemia. 165 70

More than 50% cure can be obtained with allogeneic bone marrow transplantation (BMT) when patients are transplanted in first remission of AML and ALL or chronic phase of CML. On the other hand, considerable progress has been made recently in treating acute leukemia with chemotherapy. Recent studies of intensive chemotherapy in adults with AML report approximately 40-50% 3-year disease-free survival (DFS). Accordingly, several prospective randomized clinical trials have been conducted on the use of BMT versus intensive chemotherapy in the treatment of AML. Significant differences in DFS were found only in a few studies though the results of BMT appear to be comparable or superior to chemotherapy. Therefore, the overall advantage of BMT in first remission AML is smaller than expected. We should know not whether to transplant or to perform chemotherapy, but rather whether to transplant in first remission or to perform chemotherapy first and reserve transplantation as salvage therapy. Recently acute promyelocytic leukemia has been successfully treated with differentiation therapy using all-trans retinoic acid. Low-dose aclarubicin has also been reported to be effective as differentiation therapy in some patients with myelodysplastic syndrome and atypical AML. With the advance of molecular biology of cytokines, several of them are now available for clinical use. G-CSF, GM-CSF and M-CSF are potent stimulators for the granulocyte-macrophage production; they are very effective for accelerating hematologic recovery after chemotherapy-induced myelosuppression or BMT. Interferon-alpha (IFN-alpha) has been used in the several studies. Furthermore, Ph chromosome positivity can be reduced with long-term administration of IFN-alpha; Ph-positive clone can be undetectable in some patients. Thus, IFN-alpha will be the choice of treatment for CML even if BMT is planned.
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PMID:[New trends in the treatment of leukemia]. 177 64

Two recent reports have described major clinical benefits from all-trans-retinoic acid (tRA) therapy of patients with promyelocytic leukemia (APL). This paper describes the first patient with a blast crisis of chronic myelogenous leukemia (CML-BC) who responded to oral tRA therapy. In vitro marrow studies, including clonogenic assays, immunopheno-typing, cytogenetics and premature chromosome condensation together with chromosome painting provided evidence for the in vivo differentiation and maturation of the malignant cells. The patient achieved a partial remission with reversal of all clinical features of disease, including normalization of peripheral blood counts, complete resolution of fever, fatigue and splenomegaly, and marked maturation of the bone marrow. This response to tRA in CML-BC is unique, and broadens the spectrum of diseases which may respond to retinoids.
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PMID:Treatment of promyelocytic blast crisis of chronic myelogenous leukemia with all trans-retinoic acid. 205 73

We have previously shown that a factor termed NAP-IF has the capacity to induce neutrophil alkaline phosphatase (NAP) in postmitotic granulocytes (PMGs). Recently, this factor found in cystic fluid of a human squamous cell carcinoma was shown to be identical to granulocyte colony-stimulating factor (G-CSF). In this study we examined whether NAP activity inducible with G-CSF could be modulated by other factors that are present in vivo or those that are known to induce differentiation of hemopoietic cells. Purified natural and recombinant G-CSF (nG-CSF and rG-CSF) induced NAP in PMGs from both normal individuals and patients with chronic myelogenous leukemia. Interferons (IFNs) suppressed expression of NAP by G-CSF. IFN-gamma was a potent inhibitor of G-CSF stimulation: IFN-gamma at 100 U/ml inhibited by greater than 90% the induction of NAP by G-CSF. In contrast, retinol (10(-6) M, a nearly physiological concentration) or all-trans-retinoic acid (10(-6) M) significantly enhanced NAP activity in vitro. Furthermore, the simultaneous addition of 10(-6) M retinol partially reversed the inhibitory action of IFN-gamma on the NAP induction by G-CSF. Our results suggest that NAP activity, which is often abnormal in a variety of diseases, may reflect G-CSF levels in vivo perhaps in concert with a number of other factors including IFNs and retinoids.
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PMID:Modulation by retinoids and interferons of alkaline phosphatase activity in granulocytes induced by granulocyte colony-stimulating factor. 246 68

The effects of all-trans retinoic acid (RA) were tested on the growth in vitro of myeloid progenitors from peripheral blood or bone marrow, in 25 patients with chronic myeloid leukemia (CML), ten of whom were either in accelerated or blastic phase, and in nine patients with myeloproliferative disease (MPD). The responses were compared with 12 normal bone marrow controls obtained from patients with lymphoma. Clonal growth in CML blastic and accelerated phase was inhibited to the greatest degree (mean 49 +/- 9% (SEM) of control at 0.3 microM RA). The responses in CML chronic phase and MPD were more heterogeneous, but significant inhibition was seen at higher concentrations of RA (50 +/- 12% CML chronic phase, 58 +/- 26% MPD at 3.0 microM RA). At 0.3 microM and 1.0 microM RA there were significant differences between the CML chronic phase and the CML blastic phase patients (p less than 0.02 and p less than 0.05 respectively). At these concentrations there was no significant inhibition on normal bone marrow myeloid progenitors. Inhibition was independent of the proportions of progenitors in S phase, as assessed by tritiated thymidine suicide. Preincubation of cells from selected patients with RA for 48 hours before culture in agar resulted in a significant degree of inhibition (48 +/- 8% of control). Inhibition was prevented by delaying the addition of RA from 24 to 48 hours from the beginning of the culture, indicating that RA exerts an early direct effect on myeloid progenitors.
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PMID:Inhibition by retinoic acid of myeloid progenitors in chronic myeloid leukemia and myeloproliferative disease: increased sensitivity in blastic phase of chronic myeloid leukemia. 316 96

The effect of retinoic acid (all-trans) on the clonal growth of chronic myeloid leukemia marrow was studied. The results indicate that 3 X 10(-5) M, 3 X 10(-6) M, 3 X 10(-7) M and 3 X 10(-8) M of retinoic acid inhibits the colony stimulating activity of placental conditioned medium.
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PMID:Effect of retinoic acid on bone-marrow committed stem cells (CFU-c) from chronic myeloid leukemia patients. 659 87

M195, a mouse monoclonal antibody reactive with the early myeloid antigen CD33, has been shown to target leukemia cells in patients and to reduce large leukemic burdens when labeled with 131I. A complementarity-determining region-grafted, humanized version (HuM195) has demonstrated similar targeting of leukemia cells without immunogenicity. We have studied two applications of therapy with 131I-M195. First, to intensify therapy prior to bone marrow transplantation (BMT), we combined 131I-M195 with busulfan and cyclophosphamide. Fifteen patients received first BMT for relapsed or refractory acute myelogenous leukemia or accelerated or blastic chronic myelogenous leukemia; four received second BMT for relapsed chronic or accelerated chronic myelogenous leukemia. Doses of 131I-M195 ranged from 120 to 230 mCi/m2. Few toxicities could be attributed to 131I-M195 therapy, and all patients engrafted. Eighteen patients achieved complete remission. Among those patients receiving first BMT, three have remained in unmaintained remission for 18+ to 29+ months. Six patients relapsed, including one with isolated central nervous system disease 32 months after BMT. Ten patients died in complete remission of transplant-related complications. Second, we studied whether 131I-M195 could reduce minimal residual disease and prolong remission and survival durations safely in patients with relapsed acute promyelocytic leukemia after they attained remission with all-trans-retinoic acid. Seven patients were treated with either 50 or 70 mCi/m2 131I-M195. Toxicity was limited to myelosuppression. As a measure of minimal residual disease, we monitored PML/RAR-alpha mRNA by reverse transcription PCR. Six patients had positive reverse transcription PCR assays prior to receiving 131I-M195; two converted transiently to negative. Median disease-free survival and overall survival of the seven patients were 8 (range, 3-14.5) months and 28 (range, 5.5-43+) months, respectively. This regimen compares favorably with others for relapsed acute promyelocytic leukemia. In an effort to avoid nonspecific cytotoxicity associated with 131I in future trials for minimal residual disease, we have conjugated short-range, alpha particle-emitting radioisotopes to HuM195 using a bifunctional chelate, 2-(p-isothiocyanatobenzyl)-cyclohexyldiethyl-enetriaminep entaacetic acid, with high efficiency and specific activities. 212Bi-HuM195 has demonstrated dose- and specific activity-dependent killing of HL60 cells in vitro. Injection of 213Bi-HuM195 into healthy BALB/c mice produced no effects on weight or viability.
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PMID:Radiolabeled anti-CD33 monoclonal antibody M195 for myeloid leukemias. 749 68

In this report we show a strong synergistic interaction between granulocyte colony-stimulating factor (G-CSF) and all-trans retinoic acid (ATRA) on the expression of leukocyte alkaline phosphatase (LAP) in freshly isolated acute promyelocytic leukemia (APL) blasts as well as in NB40 and HL-60 cell lines. The strong synergism observed in these cell types was not evident in two acute leukemia cell lines (K562 and GF-D8), in normal granulocytes, and in monocytes. In freshly isolated leukocytes derived from chronic myelogenous leukemia (CML), in the stable phase of the disease, a weaker interaction between ATRA and G-CSF was documented. The cross-talk between the cytokine and the retinoid was studied in detail in NB4, an immortalized APL leukemia cell line, retaining the 15-17 chromosomal translocation involving the retinoic acid receptor type alpha. The treatment of NB4 cells with G-CSF alone or ATRA alone leads to no increase and to minor induction in LAP activity, respectively. If the cells are treated with the two compounds simultaneously, a dramatic elevation of LAP is observed after 4 days. The synergism between G-CSF and ATRA is evident at concentrations of the retinoid between 10(-7) and 10(-5) mol/L and at concentrations of the cytokine between 1 and 10 ng/mL. The simultaneous presence of the two compounds is necessary to obtain maximal increase of LAP activity and the effect is cell density-dependent. Synergism is specific for G-CSF, and it is not observed with other cytokines and functional inducers of the granulocyte. The augmentation of LAP activity is the consequence of an increased transcriptional rate of the liver/bone/kidney-type (L/B/K-type) alkaline phosphatase gene, as determined by Northern blotting and nuclear run-on analysis using specific cDNA probes. Only one of the two possible alternatively spliced forms of L/B/K-type alkaline phosphatase transcript is detected in NB4 cells after stimulation with G-CSF and ATRA. This mRNA form, which is the one observed in normal polymorphonuclear leukocytes, contains the most upstream leader exon. In NB4 cells, ATRA induces G-CSF, alpha, and beta retinoic acid receptor transcripts, whereas G-CSF has minor effects on the expression of these mRNAs.
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PMID:Retinoic acid and granulocyte colony-stimulating factor synergistically induce leukocyte alkaline phosphatase in acute promyelocytic leukemia cells. 751 42

Treatment of acute promyelocytic leukemia (APL) blasts with cyclic adenosine monophosphate (cAMP) analogs, in combination with all-trans retinoic acid (ATRA), results in the upregulation of the expression of leukocyte alkaline phosphatase (LAP), a marker for the differentiation of the granulocyte. The synergistic interaction between the cyclic nucleotide analogs and the retinoid is not unique to APL cells, as it is observed also in the peripheral granulocytes of chronic myelogenous leukemia (CML) patients. The molecular mechanisms underlying LAP induction were studied in NB4, an immortalized APL cell line. Induction of LAP enzymatic activity is dependent on the time of exposure and on the concentrations of dibutyryl-cAMP or 8-bromo-cAMP and ATRA, two factors that influence the kinetics of appearance of detectable levels of the enzyme. Augmentation of LAP levels by ATRA and cAMP is the result of both transcriptional and early posttranscriptional events and requires de novo protein synthesis. LAP induction correlates with augmentation in the levels of the type I catalytic subunit of cAMP-dependent protein kinase transcript and with granulocytic differentiation. The transcriptional component of the process leading to increased LAP gene expression was reproduced in its main features by transient transfection experiments performed in COS-7 cells using the normal retinoic acid receptor type alpha (RAR-alpha) or the APL-specific aberrant form (PML-RAR) and the upstream promoter of the liver/bone/kidney (L/B/K)-type alkaline phosphatase gene. The promoter is upregulated by treatment with ATRA, and this upregulation is further increased by cAMP analogs.
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PMID:All-trans retinoic acid and cyclic adenosine monophosphate cooperate in the expression of leukocyte alkaline phosphatase in acute promyelocytic leukemia cells. 778 Jan 46


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