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

We report a woman with acute myeloid leukaemia (AML) type M2 according to FAB classification, showing a t(15;17) apparently identical to that of acute promyelocytic leukaemia (APL) on conventional cytogenetic analysis. Fluorescence in situ hybridization (FISH) using cosmidic probes specific for RAR alpha and PML, regions did not show a fusion signal as in APL. The breakpoints were assigned to 15q24.3 and 17q21.1. Detailed molecular analyses did not reveal any involvement of RAR alpha and PML genes. The patient was resistant to several front-line AMI treatments and to all-trans retinoic acid (ATRA). These findings reinforce FISH and RT-PCR as useful tools for the characterization of a t(15;17) as the translocation specifically associated with APL.
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PMID:A (15;17) translocation not associated with acute promyelocytic leukaemia. 898 49

Retinoids and vitamin D (VD) cooperate to induce the differentiation and inhibit the proliferation of human myelomonocytic leukemia cells. Two classes of retinoids receptors, the RARs and RXRs, respectively, can mediate these effects. RXR forms heterodimers with a variety of nuclear receptors, including RAR and the VD receptor. We have previously found that VD treatment increases RXR alpha levels in myelomonocytic leukemia cells. By immunoanalysis, we observed in the present work that the RAR alpha protein is expressed in proliferating U937, HL-60 and THP-1 human leukemia cells and that VD treatment induces alterations of its electrophoretic pattern, although with large differences between cell lines. In the three cell lines, 9-cis RA, an agonist of both RARs and RXRs, cooperated with VD more efficiently than all-trans RA and RAR-specific synthetic ligands, thus suggesting an involvement of both RAR and RXR pathways in cell differentiation. Using U937 cells as a model, we delineated the relative contributions of RAR and RXR by assessing the effects of receptor-selective synthetic retinoids. The synergy between VD and all-trans RA or RAR-specific agonists (TTNPB and Ro 40-6055) was abrogated by a RAR alpha-specific antagonist (Ro 41-5253), confirming an involvement of RAR alpha. However, the cooperation between VD and 9-cis RA, although reduced, was not suppressed by the antagonist, suggesting also an involvement of the RXR pathway. The role of RXR as a ligand-activated receptor was confirmed using RXR-specific agonists (CD2608 and LGD1069), which also proved able to cooperate with VD. Finally, while each synthetic agonist alone was significantly less potent than 9-cis RA, combinations of the RAR and RXR selective agonists TTNPB and LGD1069 appeared to be as effective as the pan agonist 9-cis-RA. These results confirm that various retinoids can cooperate with VD and demonstrate that, at a whole cell level, optimal effects require the activation of both RAR and RXR receptors.
Leukemia 1997 Feb
PMID:Potentiation of VD-induced monocytic leukemia cell differentiation by retinoids involves both RAR and RXR signaling pathways. 900 84

All-trans retinoic acid (RA) induces granulocytic differentiation of acute promyelocytic leukemia cells both in vivo and in vitro. In the HL-60 wild-type (WT) early promyelocytic leukemia cell line, granulocytic differentiation appears to be directly mediated by the nuclear receptor RAR alpha. An HL-60 subline resistant to RA (HL-60 R) contains a point mutation which results in a truncation of 52 amino acids at the COOH end of RAR alpha. Cross-talk between differentiation, clonal inhibition of growth and apoptosis was studied using HL-60 WT, HL-60 R, and HL-60 R infected by a retroviral vector containing RAR alpha (LX) as targets, which were cultured with various retinoids, vitamin D3 analogs, HMBA, or DMSO. None of these compounds induced significant differentiation of HL-60 R and HL-60 LX, but they did induce differentiation of HL-60 WT. In contrast, retinoids inhibited the clonal proliferation of HL-60 WT, HL-60 R, and HL-60 LX. Vitamin D3 analogs including KH1060 stimulated the clonal growth of HL-60 R; but they inhibited clonal growth of HL-60 WT and LX. Levels of Bcl-2 strongly decreased in HL-60 WT and LX after treatment by retinoids, while no change in expression occurred in HL-60 R. Neither KH 1060 nor 9-cis RA induced apoptosis of HL-60 R, but these agents did induce apoptosis in HL-60 LX WT. Taken together, we showed that HL-60 R has a global defect in its ability to be induced to differentiate by a variety of pathways, not merely the retinoid pathway. Furthermore, our HL-60 models showed that inhibition of proliferation and induction of apoptosis and differentiation can be dissociated. Clinically, these results suggest that several putative differentiation agents may have anti-cancer (antiproliferative) activities, even though they do not induce differentiation of the cancer cells.
Leukemia 1997 Mar
PMID:Alterations of differentiation, clonal proliferation, cell cycle progression and bcl-2 expression in RAR alpha-altered sublines of HL-60. 906 79

Since their introduction 15 years ago, retinoids have been increasingly used for topical and systemic treatment of psoriasis and other hyperkeratotic and parakeratotic skin disorders, keratotic genodermatoses, severe acne and acne-related dermatoses, and also for therapy and/or chemoprevention of skin cancer and other neoplasia. Oxidative metabolites of vitamin A (retinol) are natural retinoids present at low levels in the peripheral blood. Synthetic retinoids are classified into 3 generations including nonaromatic, monoaromatic and polyaromatic compounds. They are detectable in plasma 30-60 minutes after systemic administration, and reach maximum concentrations 2 to 4 hours later. Elimination half-life is 10 to 20 hours for isotretinoin, 80 to 175 days for etretinate and 2 to 4 days for, trans-acitretin; the latter, however, partially converts into etretinate. Retinoid concentrations in skin are rather low in contrast to subcutaneous fat tissue. Intracellularly, retinoids interact with cytosolic proteins and specific nuclear receptors. Two classes of nuclear receptors have been suggested to mediate retinoid activity at the molecular level, RARs and RXRs. The expression of retinoid receptors is tissue specific; skin mainly espresses RAR gamma and RXR alpha. Retinoids affect epidermal cell growth and differentiation as well as sebaceous gland activity and exhibit immunomodulatory and anti-inflammatory properties. Current retinoid research targets the development of receptor-selective retinoids for tailoring and/or improving their therapeutic profile. Currently, tretinoin is used systemically for acute promyelocytic leukaemia, etretinate and acitretin for psoriasis and related disorders, as well as other disorders of keratinisation and isotretinoin for seborrhoea, severe acne, rosacea and acneiform dermatoses. Systemic retinoids are also applied for chemoprevention of epithelial skin cancer and cutaneous T cell lymphoma. The major adverse effect of retinoids is teratogenicity; all other adverse effects are dose-dependent and controllable. Contraception is, therefore, essential during retinoid treatment in women of child-bearing age. Clinical monitoring requires physical examination for adverse effects every 3 to 4 weeks and proper laboratory investigations, also including analysis of retinoid bioavailability in selected cases. Topical retinoids are rapidly developing at present and seem promising for the future; their clinical application includes acne, aging, photodamage, precanceroses, skin cancer and disorders of skin pigmentation. The development of receptor-specific retinoids for topical treatment of psoriasis and/or acne may lead to interesting new compounds based on our current concepts of retinoid function.
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PMID:Current use and future potential role of retinoids in dermatology. 907 40

Acute promyelocytic leukemia (APL;M3) is specifically characterized by a predominance of malignant promyelocytes having atypical reciprocal translocation involving chromosome 15 and 17 [t(15;17)(q22;q11)] resulting in the fusion of retinoic acid receptor alpha (RAR alpha) on chromosome 17 and the putative transcription factor gene PML, ie the translocation generates two fusion transcripts, PML/RAR alpha and RAR alpha/PML. We describe a patient with clinical and morphologic characteristics of atypical APL but with a previously undescribed variant translocation. A 35-year-old Hispanic having atypical APL was referred for cytogenetic evaluation. The cytogenetic findings with GTG-banding coupled with FISH analysis revealed the following karyotype: 46,XX,der(9)t(1;9)(q25;q34)der(9)t(9;?)(q34;?), t(15;17)(q22;q11)ish. der(9)t(1;9)(q25;q34)(WCP1+,WCP9+),t(9;17;15)(q34;q11;q22) (WCP9+,WCP15+,PML+;WCP17+,RAR alpha +;WCP15+,WCP17+,PML-)[20]/46,XX[5]. The chromosome 17q was translocated to the chromosome 15q. However, chromosome 15q including the PML gene normally translocating to 17q and creating the RAR alpha/PML fusion gene, translocated to chromosome 9q. Does this patient have another subset of APL? Or is the genetics of APL different in cases with variant translocations as opposed to those with atypical t(15;17) translocation, though in the majority of the cases their clinical presentation remains the same.
Leukemia 1997 Apr
PMID:Variant complex translocations involving chromosomes 1, 9, 9, 15 and 17 in acute promyelocytic leukemia without RAR alpha/PML gene fusion rearrangement. 909 91

Comparison of the adherent growth inhibition of NIH:OVCAR-3 ovarian cancer cells by retinoid receptor class-selective and subtype-selective compounds with their receptor binding affinities and transcriptional activation activities indicated no correlation for RAR alpha and RAR gamma although both receptors are present. Retinoids that activated RXR alpha inhibited cell growth in the range as all-trans-retinoic acid and 9-cis-retinoic acid. The most potent inhibitor was 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN), which has been found to inhibit breast and lung cancer and leukemia cell growth and induce cancer cell apoptosis through a pathway independent of the retinoid receptors.
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PMID:Effects of receptor class- and subtype-selective retinoids and an apoptosis-inducing retinoid on the adherent growth of the NIH:OVCAR-3 ovarian cancer cell line in culture. 909 72

The malignant cells of acute promyelocytic leukemia (APL) contain a reciprocal chromosomal translocation that fuses the promyelocytic leukemia gene (PML) with the retinoic acid receptor alpha gene (RAR alpha). To test the hypothesis that the chimera PMLRAR alpha plays a role in leukemogenesis, we expressed a PMLRAR alpha cDNA in myeloid cells of transgenic mice. PMLRAR alpha transgenic mice exhibited impaired neutrophil maturation early in life, which progressed at a low frequency over the course of several months to overt APL. Both the preleukemic state and the leukemia could be transplanted to nontransgenic mice, and the transplanted preleukemia could progress to APL. The APL recapitulated features of the human disease, including a response to retinoic acid. Retinoic acid caused the leukemic cells to differentiate in vitro and in vivo, eliciting remissions of both the preleukemic state and APL in mice. Our results demonstrate that PMLRAR alpha impairs neutrophil differentiation and initiates the development of APL. The transgenic mice described here provide an apparently accurate model for human APL that includes clear evidence of tumor progression. The model should be useful for exploring the molecular pathogenesis of APL and the mechanisms of the therapeutic response to retinoic acid, as well as for preclinical studies of therapeutic regimens.
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PMID:A PMLRARalpha transgene initiates murine acute promyelocytic leukemia. 912 33

We have shown recently that a retrovirus vector expressing a natural mutant form of the PML-RAR alpha protein characteristic of human acute promyelocytic leukaemia can transform early chicken hematopoietic progenitors (Altabef et al., 1996). Neither truncated PML nor truncated RAR alpha alone could induce transformation which suggest that the two domains should cooperate for the oncogenicity of the fusion product. To further investigate the mechanisms of this co-operation, we have tested whether a truncated RAR alpha could cooperate with the v-erbB oncogene. This oncogene has previously been shown to co-operate with the rearranged thyroid hormone receptor, v-erbA, to transform erythrocytic progenitors. We show that v-erbB and a truncated RAR alpha co-operate when expressed simultaneously as independent products to transform very early chicken haematopoietic cells close to pluripotent stage. In addition, we show that v-erbB alters transcriptional abilities of RAR alpha by both enhancing its effects on RARE and reducing those on AP-1. Therefore, RAR alpha is able to co-operate with different kinds of proteins to induce transformation of early haematopoietic cells. This strongly suggests that RAR alpha are involved in the differentiation commitment of early haematopoietic progenitors during the normal process of haematopoietic differentiation. These data bring new insights in the mechanisms of oncogenic transformation by rearranged RAR alpha.
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PMID:A truncated RAR alpha co-operates with the v-erbB oncogene to transform early haematopoietic progenitors in vitro and in vivo. 913 91

All-trans retinoic acid (RA) was previously shown to regulate the growth of gastric cancer cells derived from the cell line SC-M1. This study was designed to investigate the effect of RA on the sensitivity of SC-M1 cells to lymphokine-activated killer (LAK) activity. RA at the concentration range of 0.001-10 microM was shown to induce SC-M1 cells to exhibit resistance to LAK activity in a dose-dependent manner. A kinetics study indicated that a significantly increased resistance was detected after 2 days of co-culturing SC-M1 cells with RA and reached a maximum after 6 days of culture. Similar results were obtained from two other cancer cell lines: promyelocytic leukaemia HL-60 and hepatic cancer Hep 3B. A binding assay demonstrated that the binding efficacy between target SC-M1 cells and effector LAK cells was not altered by RA. Flow cytometric analyses revealed that RA exhibited no effect on the expression of cell surface molecules, including HLA class I and class II antigens, intercellular adhesion molecule-1 and -2, and lymphocyte function antigen-3. Cell cycle analysis revealed that culture of SC-M1 cells with RA resulted in an increase in G0/G1 phase and a decrease in S phase, accompanied by a decrease in cyclin A and cyclin B1 mRNA as determined by Northern blot analysis. Additionally, RA was shown to enhance the expression of retinoic acid receptor alpha (RAR alpha) in SC-M1 cells, and to have no effect on the expression of RARbeta or RARgamma. Taken together, these results indicate that RA can significantly increase gastric cancer cells SC-M1 to resist LAK cytotoxicity by means of a cytostatic effect through a mechanism relating to cell cycle regulation. The prevailing ideas, such as a decrease in effector to target cell binding, a reduced MHC class I antigen expression or an altered RARbeta expression, are not involved.
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PMID:All-trans retinoic acid decreases susceptibility of a gastric cancer cell line to lymphokine-activated killer cytotoxicity. 915 47

All-trans retinoic acid (ATRA) induces differentiation of acute promyelocytic leukemic (APL) blasts from patients with t(15;17) APL. However, blasts from patients with the t(11;17) variant do not differentiate in response to ATRA. Our group has identified a variant of APL characterized by t(5;17) and expression of the NPM-RAR fusion gene product. From case reports it has been difficult to establish whether ATRA induces clinical responses in patients with this variant. In order to determine whether t(5;17) blasts differentiate with ATRA, we harvested mononuclear bone marrow cells from a patient with t(5;17) APL at time of relapse and cultured them in medium containing ATRA. Morphologic analysis of cytospins after 7 days of culture revealed that 60% of cells in the ATRA-treated culture had differentiated into mature neutrophilic forms, as opposed to less than 1% in the control culture. Seventy-three percent of cells acquired NBT positivity after exposure to ATRA, compared with 1% in the control culture. These results indicate that t(5;17) blasts retain the ability to terminally differentiate in response to retinoic acid.
Leukemia 1997 Jul
PMID:Differentiation of t(5;17) variant acute promyelocytic leukemic blasts by all-trans retinoic acid. 920 84


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