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

Molecularly defined specific chromosomal translocation in leukemia allows detection of minimal residual leukemia cells by the reverse transcription-polymerase chain reaction (RT-PCR). However, the positivity of the specific fusion transcripts in chronic myelogenous leukemia and acute myelogenous leukemia with t(8;21) is reportedly not directly correlated with the predictability of relapse. We analyzed seven patients with acute promyelocytic leukemia (APL) in hematological remission for PML-retinoic acid receptor alpha (PML-RAR alpha) fusion transcripts by RT-PCR with the sensitivity level of one APL cell in 10(5) bone marrow mononuclear cells. Two of the four patients with chemotherapy-induced remission had detectable PML-RAR alpha only before treatment. In the other two patients with chemotherapy-induced remission, the PML-RAR alpha was detectable when their remission was first confirmed and became negative after consolidation chemotherapy. Two patients were resistant to chemotherapy and achieved remission by all-trans-retinoic acid; PML-RAR alpha was detectable in them for a few months during consolidation chemotherapy. Two patients whose PML-RAR alpha had become continuously positive had relapse 2 and 8 months later, but the other five patients with continuously negative or only transiently positive PML-RAR alpha remained in remission during follow-up for 11 to 35 months. These findings suggest the relevance of detectable PML-RAR alpha by RT-PCR to the predictability of relapse in acute promyelocytic leukemia.
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PMID:PML-RAR alpha fusion transcripts by RNA PCR in acute promyelocytic leukemia in remission and its correlation with clinical outcome. 785 39

Granulocyte-macrophage colony forming units (CFU-GM) from patients with advanced stage chronic myelogenous leukemia (CML), i.e. in blastic crisis (BC) or accelerated phase (AP), were inhibited by all-trans-retinoic acid (tRA) approximately 1000-fold more potently than those from chronic phase (CP) CML patients (median IC50 = 10(-9) M tRA for six CML-AP/BC cases vs > 10(-6) M tRA for seven CML-CP cases). A similar activity pattern was observed for the stereoisomer 13-cis-RA (cRA). There was no apparent correlation of CFU-GM retinoid sensitivity with cloning efficiency or other colony characteristics. Interferon alpha-2a (INF alpha) alone strongly inhibited CFU-GM growth in all four CML-AP/BC cases (IC50 < or = 250 IU/ml) and three out of seven CML-CP cases (IC50 < or = 500 IU/ml), but there was little or no interactive effect between various concentrations of tRA and INF alpha (50 IU/ml) on CFU-GM from either CML-AP/BC or CML-CP cases. These results suggest that CML-AP/BC CFU-GM have some intrinsic molecular alteration(s) which markedly enhances their responsiveness to tRA and cRA, which may be clinically exploitable.
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PMID:Effect of retinoic acid and interferon alpha on granulocyte-macrophage colony forming cells in chronic myeloid leukemia: increased inhibition by all-trans- and 13-cis-retinoic acids in advanced stage disease. 793 31

This paper describes the treatment of promyelocytic blast crisis of chronic myelogenous leukemia with all-trans-retinoic acid (ATRA). The patient, a 22-year-old male, was diagnosed to have APL and had been treated with busulfan and then with three and half years interferon (IFN) alpha in the chronic phase. A cytogenetic study of blast cells showed the t(1;17) (p11;q11) translocation as the second chromosomal abnormality without morphological abnormality of chromosome 15. Molecular analysis showed cells to have a chimera gene consisted of PML and retinoic acid receptor alpha genes. Though maturation and differentiation of leukemic cells were seen after ATRA therapy, hematological complete remission did not occur. The ineffectiveness of ATRA may be dut to different pathological conditions from de novo APL, or progressive reduction in plasma ATRA concentration as reported by Muindi et al. When our case was compared with a similar case reported by Wiernick et al., both cases were treated with IFN alpha in the chronic phases, had no t(15;17) translocation involving No.1 chromosome abnormality and did not develop complete remission after ATRA therapy.
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PMID:[Treatment of promyelocytic blast crisis of chronic myelogenous leukemia with all-trans-retinoic acid]. 813

The translocation t(15;17)(q22;q21) is seen exclusively in patients with acute promyelocytic leukemia (APL) and in the promyelocytic blast crisis of chronic myeloid leukemia (CML). This translocation juxta-poses the promyelocytic leukemia (PML) gene on chromosome 15 and the retinoic acid receptor-alpha (RARA) gene on chromosome 17, resulting in the formation of a chimeric mRNA transcript. We describe a patient with the microgranular variant form of APL, with no detectable cytogenetic abnormality of either chromosomes 15 or 17, who nevertheless had juxtaposition of PML and RARA genes and expressed a chimeric transcript. Conventional cytogenetics showed the karyotype 46,XY,d-er(3)t(3;8)(p25;q12). Fluorescent in situ hybridization (FISH) with paints for chromosomes 8, 15, and 17 confirmed the presence of structurally intact chromosomes 15 and 17 and trisomy for chromosome 8q. Nevertheless, FISH using cosmid probes for PML and RARA showed their juxtaposition on one chromosome 15 homolog. Both genes were also present on their normal homologs; in addition, part of the RARA gene was still present on the remaining chromosome 17. DNA analysis by Southern blotting, performed with a variety of probes including PML, RARA and retinoic acid receptor-beta (RARB), showed a rearrangement in PML. Reverse transcriptase polymerase chain reaction (RT-PCR) confirmed the existence of hybrid transcripts of 276, 455 bp and 623 bp, from PML-RARA on the der(15) chromosome, consistent with alternate exon splicing of the long form of the transcript occurring in 50% to 60% of patients with APL. Our results show that APL patients with cytogenetically normal chromosomes 15 and 17 may, nevertheless, have involvement of both PML and RARA genes defining a subgroup of APL, t(15;17)-negative/PML-RARA-positive which is analogous to Philadelphia chromosome-negative/BCR-ABL-positive CML. In this case, the presence of chimeric transcripts suggests that treatment with all-trans RA may be warranted in APL, even in the absence of detectable cytogenetic change, showing the usefulness of RT-PCR or FISH to aid diagnosis.
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PMID:Interstitial insertion of retinoic acid receptor-alpha gene in acute promyelocytic leukemia with normal chromosomes 15 and 17. 818 Mar 90

Clonality studies of hematopoietic reconstitution after remission were performed in 24 female patients (pts) with leukemias characterized by specific molecular markers. At diagnosis, 13 pts had promyelocytic leukemia (PML) retinoic acid receptor-alpha (RAR-alpha)-rearranged acute promyelocytic leukemia (APL), 8 Philadelphia positive (Ph'+) break-point cluster region (BCR+) chronic myeloid leukemia (CML), and 3 Ph'+ (BCR+) acute lymphoblastic leukemia (ALL). All pts were analyzed at presentation and after Southern blot suppression of specific rearrangements after various treatments, including conventional chemotherapy, autologous or allogeneic bone marrow transplant (BMT), all-trans retinoic acid, and alpha-2b interferon. DNA from BM samples collected at diagnosis and, during remission phases, were subjected to Southern blot analysis with the M27 beta probe to detect X chromosome methylation differences, and with BCR, in CML and ALL cases, or PML/RAR-a probes for gene rearrangements, in APL cases. Twenty-one of the 24 pts had polyclonal methylation patterns at remission, together with disappearance of the specific rearrangement, whereas 3 pts retained the same single unmethylated DXS255 allele detected at diagnosis despite no evidence of gene rearrangement. Concerning these 3 pts, such an apparently clonal pattern was also observed in one case in T lymphocytes and skin-derived DNA; in a second case in BM fibroblasts and T lymphocytes; and, in the third case, in blood mononuclear cells obtained from her healthy female BM donor. All these 3 pts are in unmaintained clinical and cytogenetic remission after more than 20 months off therapy. These data suggest that (1) polyclonal and presumably normal hematopoiesis occurs in APL, CML, and Ph'+ ALL pts once the major burden of leukemic cells carrying a specific rearrangement is suppressed by treatment; and (2) unbalanced X chromosome methylation patterns, or aberrant methylation of X chromosome regions may be observed in some cases, most likely reflecting constitutional features simulating a clonal picture.
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PMID:Polyclonal hematopoietic reconstitution in leukemia patients at remission after suppression of specific gene rearrangements. 832 93

The membrane expression of CD45RA and CD45RO on fresh leukaemic cells taken from 529 cases of acute haemopoietic malignancies, including 117 B-origin acute lymphoblastic leukaemia (B-origin ALL), 37 T-origin acute lymphoblastic leukaemia (T-origin ALL0, 297 de novo acute myeloid leukaemia (AML), 42 refractory anaemia with excess of blasts in transformation (RAEB-T) and 36 myeloid blastic phase of chronic myelogenous leukaemia (CML-BP-my), was analysed. B-origin ALLs were characterized by the lack of the RO isoform along with the consistent presence of RA. Conversely, a differential expression of the two isoforms was detected in different subsets of T-origin ALL, in that T-stem cell leukaemias (T-SCL: CD7+, CD4-, CD8-, CD1-) preferentially expressed CD45RA whereas conventional T-acute lymphoblastic leukaemias (T-ALL: CD7+, CD4+ and/or CD8+ and/or CD1+) were consistently marked by CD45RO. Within myeloid malignancies, most of AMLs displayed CD45RA, while a substantial group of CML-BP-my preferentially exhibited CD45RO. As a general rule, a reciprocal exclusion of the two isoforms was observed in AML as well as in ALL. Nevertheless, a frequent coexpression of CD45RA and CD45RO was observed in CD14+ AML. In vitro treatment with all-trans retinoic acid (ATRA) was able to promote a switch from CD45RA to CD45RO expression in 27 de novo AML, independently from morphological subtyping. To our knowledge, this is the first report on CD45 isoform expression in a large series of patients with acute leukaemia. The knowledge of the differential expression of CD45RA and CD45RO can ameliorate our classificative approach to haematological malignancies, as well as disclose new multiple overlap points between normal and leukaemic cell differentiation.
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PMID:Expression of the leucocyte common antigen (LCA, CD45) isoforms RA and RO in acute haematological malignancies: possible relevance in the definition of new overlap points between normal and leukaemic haemopoiesis. 854 36

RT-PCR assays used to detect acute promyelocytic leukemia (APL) are generally considered less sensitive than those for other hematological malignancies, such as CGL. Most patients with APL express del(17q)-derived RAR alpha-PML transcripts as well as the putative leukemogenic PML-RAR alpha associated with add(15q). We have found that a nested RT-PCR for RAR alpha-PML affords greater sensitivity than that for PML-RAR alpha, particularly in patients with the commonest breakpoint pattern. Therefore, we have evaluated both assays in parallel to monitor a group of 12 de novo APL patients who relapsed despite treatment with both all-trans retinoic acid (ATRA) and chemotherapy. 5' (bcr 3) breakpoints in PML were over represented among the group and three patients had complex cytogenetic abnormalities suggesting both factors may increase the risk of relapse. The RAR alpha-PML assay changed the PCR status of two patients in morphological remission; in both cases disease contamination of bone marrow harvest specimens was detected. Although parallel assessment of PML-RAR alpha and RAR alpha-PML can enhance minimal residual disease detection in APL, this study demonstrates that treatment strategies involving determination of PCR status post-consolidation, even using RAR alpha-PML in addition to the more conventional PML-RAR alpha assay will fail to identify all patients at risk of relapse. Whether the duration of PCR positivity is a helpful prognostic indicator in those patients who ultimately become PCR negative is being addressed by
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PMID:Minimal residual disease detection in acute promyelocytic leukemia by reverse-transcriptase PCR: evaluation of PML-RAR alpha and RAR alpha-PML assessment in patients who ultimately relapse. 855 40

We investigated the effect of all-trans retinoic acid (ATRA) alone and in combination with interferon-alpha (IFN-alpha) on the granulocyte-macrophage (GM) colony formation of peripheral blood progenitors isolated from patients with chronic myeloid leukemia (CML) (n = 12) or other myeloproliferative disorders (n = 10) as well as from healthy controls (n = 7). The ATRA or IFN-alpha alone inhibited slightly, but not significantly, the GM colony growth in CML. Granulocyte-macrophage colony formation decreased significantly (P<0.05) when ATRA and IFN-alpha were combined (114 +/- 96 versus 74 +/- 53 colonies/10(4) mononuclear cells). The combination did not have any inhibitory effect on the other MPDs. In healthy controls, ATRA or IFN-alpha alone or their combination stimulated GM colony growth, the increase being from 22 +/- 9 to 39 +/- 16 colonies for ATRA (P<0.05), up to 47 +/- 12 colonies for IFN-alpha (P<0.05) and up to 50 +/- 19 colonies for the combination (P<0.05). In conclusion, ATRA combined with IFN-alpha inhibits GM colony growth in CML. This combination may be worth testing clinically as a treatment of CML.
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PMID:All-trans retinoic acid combined with interferon-alpha effectively inhibits granulocyte-macrophage colony formation in chronic myeloid leukemia. 863 19

Clonal proliferation in agar, cell maturation and cell cycle characteristics were studied on peripheral blood cells from a patient with chronic myeloid leukaemia (CML) in blast crisis. Studies were performed in normal conditions and after incubation with all-trans retinoic acid 10(-6) M. At the time of the study the patients showed 300 x 10(9)/leukocytes/L (40% blast and promyelocytes). Cytogenetic studies showed 90% metaphases with t (9; 22) and t (18; 21). DNA index was 1.36. In agar cultures 450 CFU/2 x 10(5)/L cells, plus abnormal clusters were obtained, in the presence of conditioned media, and 115 normal CFU-GM after addition of all-trans retinoic acid 10(-6)M. Addition of retinoic acid to cellular suspension in liquid cultures decreased the number of immature cells from 20 to 2% in 5 days and decreased the number of cells in "S" phase from 33 to 11% after 8 days. These results show cytodinamic abnormalities in patients with CML in blast crisis and potential reversibility of these alterations by all-trans retinoic acid.
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PMID:[Blast differentiation in a patient with chronic myeloid leukemia in blast crisis using retinoic acid]. 885 Feb 36

Human chronic myelogenous leukemia-blast crisis K562 cells have been demonstrated to be relatively resistant to antileukemic drug-induced apoptosis. This has been attributed to the activity of p210bcr-abl tyrosine kinase present in the K562 cells, which is known to suppress drug-induced apoptosis. Recently, K562 cells have been shown to express the antiapoptosis Bcl-xL but not Bcl-2 proteins. To investigate the contribution of Bcl-xL toward resistance to drug-induced apoptosis, we created K562/Bcl-xS and K562/neo cells by electroporating the expression plasmids pSFFVneo-Bcl-xS and pSFFVneo, containing the bcl-xS and neomycin resistance genes, respectively, into K562 cells. K562/Bcl-xS but not K562/neo cells expressed the bcl-xS mRNA and p19Bcl-xS protein. In contrast, both cell types expressed equivalent levels of Bcl-xL, Bax, Bcl-2, Myc, retinoblastoma, p21cbor-abl, and p145abl proteins. A significant increase in the hemoglobin levels was observed in the K562/Bcl-xS compared with the K562/neo cells (P < 0.05). In addition, K562/Bcl-xS cells were significantly more sensitive than K562/neo cells to undergoing erythroid differentiation induced by low-dose 1-beta-D-arabinofuranosylcytosine (ara-C) and hexamethyl bisacetamide (P < 0.05), but not by all-trans-retinoic acid. Low-dose ara-C- or hexamethyl bisacetamide-induced differentiation was not associated with apoptosis of K562/Bcl-xS or K562/neo cells. Low-dose ara-C-induced erythroid differentiation was accompanied by conversion of the retinoblastoma protein to predominantly its underphosphorylated isoform as well as by down-regulation of Myc levels in K562/Bcl-xS and K562/neo cells. Importantly, exposure to high-dose ara-C (HIDAC; 100 microM ara-C for 4 h) caused internucleosomal DNA fragmentation and the morphological features of apoptosis in K562/Bcl-xS cells. These effects were modestly enhanced by cotreatment with HIDAC plus herbimycin A. In contrast, K562/neo cells were completely resistant to HIDAC- and herbimycin A-induced apoptosis. These results indicate that the expression of Bcl-xS induces erythroid differentiation and partially sensitizes chronic myelogenous leukemia-blast crisis-derived K562 cells to ara-C-induced differentiation and apoptosis.
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PMID:Enforced expression of Bcl-XS induces differentiation and sensitizes chronic myelogenous leukemia-blast crisis K562 cells to 1-beta-D-arabinofuranosylcytosine-mediated differentiation and apoptosis. 895 29


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