[All-trans retinoic acid therapy in acute promyelocytic leukemia--current status and prospect].
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Antineoplastic Agents↗
Biomedical subjects
T Naoe
Publications and source records attributed to T Naoe.
Analysis of the joining sequences of the t(15;17) translocation in human acute promyelocytic leukemia: sequence non-specific recombination between the PML and RARA genes within identical short stretches.
Molecular analysis of the t(15;17) translocation in 70 patients with acute promyelocytic leukemia (APL) confirmed that the breakpoints of chromosome 15 were located in two regions of the promyelocytic leukemia (PML) gene, mainly introns 3 and 6, whereas the breakpoints of chromosome 17 were consistently in intron 2 of the retinoic acid receptor alpha (RARA) gene. To study the reason for the clustering of the breakpoints and the underlying mechanism of the chromosomal translocation, we characterized the joining sequences of der(15) and der (17) by polymerase chain reaction in samples from eight patients with APL. There was no cluster of the breakpoints within the introns, and no consensus sequence-motif was found around them. One or nine extra nucleotides were inserted into two joining sites. There were identical stretches of one to seven nucleotides between the PML and RARA genes in the majority of the joining sequences. These data provide a potential model of the t(15;17) translocation: random DNA double strand cleavage, modification of DNA ends by enzymes including terminal deoxynucleotidyl transferase, and single strand base-pairing within identical short stretches. Furthermore, APL develops only when the PML and RARA genes are rearranged, within restricted genomic regions and a functional PML-RARA chimeric product is produced, and this might lead to a clustering of the breakpoints.
Base Sequence↗
Comparable profiles of the immunoglobulin heavy chain complementarity determining region (CDR)-3 in CD5+ and CD5- human cord blood B lymphocytes.
It has been suggested that CD5+ B cells are closely related to the pathogenesis of autoimmune disease or chronic lymphocytic leukaemia, whereas the origin and physiological role of CD5+ B cells remain controversial. To study the molecular differences between CD5+ and CD5- B cells in terms of immunoglobulin gene structure, we sorted both subsets from new-born cord blood and analysed the complementarity determining region (CDR)-3 profiles of the immunoglobulin heavy chain (IgH) gene. The CDR-3 sequences from both CD5+ and CD5- B cells represented the same incidence and length of N-region, and the same usage of D and JH segments. When translated into amino acids, 24 of 32 clones (75%) and 25 of 37 clones (65.8%) from their respective subset were productive, and the composition of the deduced amino acids were similar between both subsets. These data suggest that CD5+ B cells are not a distinct lineage presenting a biased immunoglobulin repertoire in B cells.
Amino Acid Sequence↗
Isoforms of PML-retinoic acid receptor alpha fused transcripts affect neither clinical features of acute promyelocytic leukemia nor prognosis after treatment with all-trans retinoic acid. The Leukemia Study Group of the Ministry of Health and Welfare (Kohseisho).
All-trans retinoic acid (ATRA) has been used as a potent differentiation drug for acute promyelocytic leukemia (APL). Although the mechanism of its effectiveness upon APL remains unclear, the PML-retinoic acid receptor alpha (RARA) chimeric protein produced by t(15;17) is assumed to underlie the sensitivity of APL cells to ATRA. There are two major isoforms of PML-RARA transcripts; short (S) and long (L), according to the breakpoints in the PML gene. We therefore compared the clinical variables, the response to ATRA and the prognosis between 28 patients with type S and 68 patients with type L. Patients were treated in multi-institutional trials with ATRA, and chemotherapy was combined when peripheral blasts and leukocyte counts increased during the therapy. The clinical features at diagnosis were similar between the two molecular subtypes, and there was no significant difference in remission induction rates; 86% for the type S group and 90% for the type L group. There was no statistical difference in overall survival and CR duration as well as disease-free survival (DFS). In newly diagnosed patients, predicted 2-year DFS was 66% for the type S group and 67% for the type L group. In refractory or relapsed patients, it was 19 and 23%, respectively. These data indicated that isoforms of PML-RARA fused transcripts affect neither the clinical features of APL nor the prognosis after treatment with ATRA.
Adolescent↗
Delayed or insufficient restoration of PML and PML-RAR alpha subcellular localization after exposure in vitro to retinoic acids in all-trans retinoic acid-resistant APL cells.
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Drug Resistance↗
[Characterization of the immunoglobulin heavy and light chain variable region sequences from human multiple myeloma cells].
Although multiple myeloma (MM) morphologically represents the terminal B cell differentiated stage as a plasma cell, it remains controversy that MM cells have arisen from a B cell at which stage of B cell development. The immunoglobulin heavy chain (IgH) variable region genes can serve as markers in clonal analysis because unique combinations of VH, D and JH gene elements and as a genealogical record of clonal selection and expansion, and molecular diversification during maturation of the immune response. We analyzed the IgH variable region sequences from human MM cells. Furthermore, to compare with normal bone marrow (BM) plasma cell repertoire, we determined the IgH variable region sequences of PCR amplified cDNA libraries consisting of C mu, C gamma, and C alpha transcripts from human normal BM cells. The VH segments in MM cells, except for Bence-Jones protein (BJP) type, were extensively mutated, and the characteristic structure of the IgH variable region essentially reflect those from normal BM C gamma and C alpha transcripts. Although the replacement/silent (R/S) mutation ration in MM cells was under the value which reflect antigen selected substitutions, such a lower value was also observed in normal BM C gamma and C alpha transcripts, suggesting that the transformation of MM dose not necessarily take place before the antigen-dependent selection, rather can after clonal expansion. However, BJP type MM might arise from an earlier stage of B cell development than the other types because of lower incidence of somatic mutation in their VH segments which was the same as normal BM C mu transcripts.
Humans↗
Prognostic significance of the RT-PCR assay of PML-RARA transcripts in acute promyelocytic leukemia. The Leukemia Study Group of the Ministry of Health and Welfare (Kouseisho).
Minimal residual disease (MRD) was prospectively monitored at the 10(-5) level by the reverse transcriptase-polymerase chain reaction (RT-PCR) of PML-retinoic acid receptor alpha (RARA) transcripts from 27 acute promyelocytic leukemia (APL) patients who achieved complete remission (CR) with all-trans retinoic acid and chemotherapy (previously untreated patients, 15; refractory to chemotherapy or relapsed, 12). The RNA quality from bone marrow cells was firstly assessed by gel electrophoresis to avoid false negativity because of the fragility of the APL cells and the PML-RARA transcripts. In 12 of 15 untreated patients, RT-PCR became negative during consolidation and intensification therapy 4-16 months after the initiation of therapy, whereas it remained positive in nine of 12 refractory patients. At the end of therapy, RT-PCR was negative in 14 patients and positive in 13 patients. The former patients remained in CR at median follow-up of 9 months after the end of therapy. In the latter, however, 10 patients relapsed at a median of 5 months after the end of therapy. These results suggest that the RT-PCR assay can evaluate the quality of CR in APL and predict subsequent relapse.
Adult↗
Continuing immunoglobulin heavy chain gene rearrangements in chronic myeloid leukemia with recurrent B-lymphoid blast crises after bone marrow transplantation.
We sequentially analyzed the immunoglobulin heavy chain variable (IgH V) region gene of leukemia cells obtained from a chronic myeloid leukemia (CML) patient who had three episodes of B-lymphoid crisis after bone marrow transplantation. Southern blot analysis using the JH probe showed different rearranged bands at each crisis, although the same rearranged bands of the BCR gene were observed. We amplified and sequenced the IgH V region gene of the leukemia cells by reverse transcriptase polymerase chain reaction (RT-PCR) using the primers corresponding to the consensus 5'VH and mu constant regions. The dominant leukemia clone at each crisis had a unique VH-D-JH rearrangement; VH4A (V79)-DLR2-J5 (clone-1), VH4B (DP70)-DK4-J6 (clone-2) and VH4A (V79)-DN4-J6 (clone-3) at the first, second and third crises, respectively. Further analysis by PCR amplification using the consensus 5'VH and clone-specific primers revealed that clone-1 underwent VH4-->VH3 replacement at the second crisis, and that clone-3 was already in existence at the first crisis. Moreover, the DN4-J6 joining clone, in which the sequence was the same as that of clone-3, was identified at the first and third crises by PCR amplification using primers corresponding to the region upstream of the DN4 segment and DN4-J6 boundary of clone-3. These observations suggest that multiple clones were generated from the progenitor cells of blast crisis, which were transformed at a very early stage of B-lymphocyte ontogeny, by continuing rearrangement mechanisms of the IgH genes, and that the dominant clone at each crisis was undergoing change.
Adult↗
Effect of retinoic acid isomers on proliferation, differentiation and PML relocalization in the APL cell line NB4.
Retinoic acids exert a wide physiological role in development and differentiation. Retinoic acids have also been used in the treatment of human cancers, particularly in acute promyelocytic leukemia (APL). A structure-function relationship of the RA isomers in terms of clinical effect has been observed since all-trans retinoic acid (ATRA) induces a high complete remission rate while 13-cis retinoic acid (13-cis RA) shows much poorer effect. In this study, we examined the effect of RA isomers, including ATRA, 13-cis RA and 9-cis RA, on the proliferation and differentiation of NB4 cells. A number of parameters such as cell growth curve, dynamics of cell cycle, expression of clusters of differentiation and reduction of nitro blue tetrazolium (NBT) as well as immunofluorescence staining of PML were used to evaluate the effects of three isomers at two concentrations (10(-8) M and 10(-7) M). It has been shown that during the first 48 h of RA treatment, the APL cell differentiation was coupled with the cell proliferation. Although similar effects of proliferation inhibition and differentiation induction were observed among the three isomers at 10(-7) M, significant differences appeared at a concentration of 10(-8) M, 9-cis RA showed a higher activity than that of ATRA, while ATRA showed better results than 13-cis RA. Our results provide further evidence that 9-cis RA could be a promising molecule in differentiation induction of malignant cells.
Antigens, CD↗
Bone marrow transplantation in 614 patients: twenty year experience of the Nagoya Bone Marrow Transplantation Group (NBMTG).
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Anemia, Aplastic↗
Detection of minimal residual disease in patients with childhood common acute lymphoblastic leukemia after autologous bone marrow transplantation with ex vivo purging and systemic IL-2 infusion: unsuccessful prediction of subsequent relapse.
We sequentially analyzed minimal residual disease (MRD) in 7 children with common acute lymphoblastic leukemia (cALL) after autologous bone marrow transplantation (ABMT) with ex vivo purging followed by systemic interleukin-2 infusion. After ABMT, 3 of the 7 patients remained in complete remission (CR) for more than 1 year, and 4 subsequently relapsed. MRD was estimated by polymerase chain reaction amplification to detect the leukemia clone-specific immunoglobulin heavy chain third complementarity determining region (IgH CDR-III). The IgH CDR-III sequences from the relapsed patients were identical with those determined at each respective initial diagnosis. In 2 patients, the levels of MRD were 10(-2) and 10(-5) in the harvested bone marrow (BM) cells, and even after purging the levels were 10(-4) and 10(-5) cells, respectively. One of the 2 patients relapsed 3 months after ABMT, while the other remained in CR for 33 months after ABMT. Among the 4 patients who subsequently relapsed after ABMT, MRD was not detected in the BM samples even 1 month before relapse. Our results suggest that PCR-negativity does not necessarily indicate a lower risk of subsequent relapse. Detection of MRD tends to favor the assessment of the therapeutic effects rather than prediction of relapse.
Base Sequence↗
[Efficacy of early administration of G-CSF after intensive chemotherapy in acute leukemia: a randomized controlled trial. Tokai Infection Study Group on Hematological Disorders].
The effect of granulocyte colony-stimulating factor (G-CSF) on neutropenia and infection was studied in a randomized trial in patients receiving intensive chemotherapy for acute leukemia. Fifty seven patients with acute leukemia (35 cases of refractory acute myeloid leukemia, 19 cases of acute lymphoblastic leukemia and 3 cases of blast crisis of chronic myeloid leukemia) were given G-CSF under either of the following two conditions; 1) Group A: starting G-CSF (200 micrograms/m2iv) administration 24 hrs after chemotherapy. 2) Group B: the same dose of G-CSF administration after a febrile episode of 38 degrees C with neutropenia (less than 1,000/microliters). Five patients were excluded from the study. Group A (27 patients) showed a shorter febrile period (2.15 +/- 2.98 days) than the 25 patients of Group B (3.40 +/- 4.78 days), but the difference was not statistically significant. Compared to Group B, Group A showed significantly early recovery of neutrophil counts as well as early recovery from documented infections. There was no evidence that early administration of G-CSF accelerates the growth of leukemic cells nor causes early relapse of acute leukemia.
Acute Disease↗
Bernard-Soulier syndrome Kagoshima: Ser 444-->stop mutation of glycoprotein (GP) Ib alpha resulting in circulating truncated GPIb alpha and surface expression of GPIb beta and GPIX.
The platelet membrane glycoprotein (GP)Ib/IX complex is composed of three polypeptides, GPIb alpha, GPIb beta, and GPIX, and functions as a platelet receptor for von Willebrand factor. All three subunits are reported to be requisite for efficient surface expression of the complex. The absence of the GPIb/IX complex on platelet membrane is the hallmark of a congenital qualitative platelet disorder, termed the Bernard-Soulier syndrome (BSS). We describe here the molecular basis of a novel variant phenotype of BSS in a female patient, designated as BSS Kagoshima. Her platelets completely lacked the surface expression of GPIb alpha, but expressed a residual amount of GPIb beta and GPIX. Unexpectedly, her platelets and plasma contained a truncated GPIb alpha polypeptide with an apparent molecular weight of 116 kD (under nonreducing conditions). The amounts of truncated protein were 23% and 60% of the normal values in platelets and plasma, respectively. The abnormal protein contained a normal amount of sialic acid as demonstrated by digestion with neuraminidase. DNA sequencing analysis showed a homozygous single nucleotide substitution from the serine codon (TCA) to a nonsense codon (TAA) at residue 444 in the GPIb alpha gene. The mutant gene generated a truncated GPIb alpha molecule lacking the transmembrane region and cytoplasmic tail. Her parents were heterozygotes for the mutation. These findings suggest that this type of truncated GPIb alpha was produced, normally glycosylated, and subsequently secreted into the plasma. Furthermore, the truncated GPIb alpha might be associated with the process of the surface expression of incomplete GPIb/IX complex, GPIb beta and GPIX.
Adult↗
A double-blind controlled study of granulocyte colony-stimulating factor started two days before induction chemotherapy in refractory acute myeloid leukemia. Kohseisho Leukemia Study Group.
We conducted a prospective, double-blind controlled study to determine the efficacy of a recombinant granulocyte colony-stimulating factor (G-CSF, 200 microgram/m2) starting daily from 2 days before an induction therapy until neutrophils recovered to above 1,500/microL or until 35 days after the therapy in 58 patients with relapsed or refractory acute myeloid leukemia (AML). Twenty-eight patients in the G-CSF group showed significantly faster recovery of neutrophils (P < .001) than 30 patients in the placebo group. The incidence of febrile episodes and of documented infections was almost the same in both groups. However, among 39 patients who did not show any infectious episodes during the 2-week period after the start of chemotherapy, the incidence of documented infections after the third week tended to be lower in the G-CSF group, but not statistically significantly. There was no evidence that G-CSF stimulated the growth of AML cells in the bone marrow during the 2-day period before the chemotherapy, nor that G-CSF accelerated the regrowth of AML cells during the 5-week period after the therapy. Fifty percent of patients in the G-CSF group and 37% in the placebo group had complete remission (CR). Although the rate was higher in the G-CSF group, the difference was not statistically significant (P = .306). There was no difference between the two groups in event-free survival of all patients and in disease-free survival of patients who had achieved CR.
Adolescent↗
Activation and destruction of platelets in patients with rheumatic heart disease.
We evaluated the activation and destruction of platelets in 24 patients with rheumatic heart disease (RHD) involving the mitral valve. Ex vivo platelet aggregation induced by adenosine diphosphate (ADP) and collagen was significantly increased in RHD patients as compared with normal controls. Plasma levels of beta-thromboglobulin (beta-TG) and platelet factor 4 were also elevated. Plasma concentrations of glycocalicin, a proteolytic fragment of platelet membrane glycoprotein Ib, were increased, while platelet counts were decreased in RHD patients as compared with normal controls. RHD patients with, versus those without, atrial fibrillation demonstrated significant differences in beta-TG levels and platelet counts. However, we observed no difference in glycocalicin levels between the two groups. The present study demonstrated that increased platelet activation, as well as platelet destruction, occur in patients with RHD.
Adult↗
Characterization of immunoglobulin heavy chain gene rearrangements in chronic myeloid leukemia with recurrent B-lymphoid blast crisis following bone marrow transplantation.
We sequentially analyzed the immunoglobulin heavy chain (IgH) variable region gene of leukemia cells obtained from a chronic myeloid leukemia (CML) patient who had three episodes of B-lymphoid crisis after bone marrow transplantation. Southern blots using the JH probe showed a single rearranged band which differed at each crisis, although the rearranged bands of the BCR gene were the same at each crisis. The IgH variable region sequences of the leukemia cells at each crisis were different. These observations suggested that multiple clones were generated from the progenitor cells of the blast crisis, which were transformed at a very early stage of B-lymphocyte ontogeny.
Adult↗
[A comparative clinical study on flucytosine alone and in combination with fluconazole in hematological malignancies: a multicenter study using the envelope method].
Two different flucytosine (5-FC) treatment regimens, one by itself and the other in combination with fluconazole (FLCZ) were compared in chemotherapy against mycotic infections in 60 patients with hematological diseases. The patients in a randomized fashion were assigned to the two treatments. In the combination regimen, the two drugs were used in half doses. beta-D-Glucan and D-arabinitol in the sera of patients were measured to document mycotic infections, and bacterial examinations were also performed. The efficacy of the combination therapy was 60.0% (18/30) and that of 5-FC alone was 65.5% (19/29). The stratified evaluation indicated that no factor was found to contribute to the efficacy in the two treatments with statistical significance. The side effects occurred in few cases and none of those was serious; including, one case of subjective symptom in each groups and two episodes of liver dysfunction in combination treatment. Changes in beta-D-glucan concentrations in the sera reflected well the pathophysiology of mycotic infections and clinical improvement. These results suggested that a combination of 5-FC and FLCZ at half doses provided a clinical benefit comparable to 5-FC alone at the ordinary dose, and the safety was considered satisfactory.
Adult↗
[New strategy for diagnosis and treatment of acute promyelocytic leukemia with t (15;17)].
All-trans retinoic acid (ATRA)-therapy against acute promyelocytic leukemia (APL) is epoch-making in the sense of the first success in both tumor-differentiation therapy and molecule-targeted therapy. Kouseishou APL-study group performed three clinical studies to refractory APL with ATRA from 1990 to 1993. Complete remission (CR) was obtained in 82%, 88% and 78% of 22, 41 and 46 patients, respectively. Molecular diagnosis of the t (15;17) translocation was possible using Southern blot analysis and reverse transcriptase polymerase chain reaction (RT-PCR).
Chromosomes, Human, Pair 15↗