-
S Kako,
S Morita,
H Sakamaki,
H Iida,
M Kurokawa,
K Miyamura,
H Kanamori,
M Hara,
N Kobayashi,
Y Morishima,
K Kawa, T Kyo,
T Sakura,
I Jinnai,
J Takeuchi,
Y Miyazaki,
S Miyawaki,
K Ohnishi,
T Naoe,
Y Kanda
[show abstract]
[hide abstract]
ABSTRACT: The efficacy of unrelated transplantation for patients with ALL who lack an HLA-matched sibling remains unclear. We performed a decision analysis to determine the efficacy of myeloablative transplantation from a genetically HLA-A, -B, -DRB1 allele-matched unrelated donor for patients with Ph chromosome-negative ALL aged 21-54 years. The transition probabilities were estimated from the Japan Adult Leukemia Study Group studies (ALL93; n=80, ALL97; n=82), and the Japan Marrow Donor Program database (transplantation in first CR (CR1): n=177). The primary outcome measure was the 10-year survival probability with or without quality of life (QOL) adjustment. Subgroup analyses were performed according to risk stratification based on the WBC count and cytogenetics, and according to age stratification. In all patients, unrelated transplantation in CR1 was shown to be superior in analyses both with and without QOL adjustment (40.8 vs 28.4% and 43.9 vs 29.0%, respectively). A similar tendency was observed in all subgroups. The decision model was sensitive to the probability of leukemia-free survival following chemotherapy and the probability of survival after transplantation in standard-risk and higher-aged patients. Unrelated transplantation in CR1 improves the long-term survival probability in patients who lack an HLA-matched sibling. However, recent improvements in treatment strategies may change this result.Bone Marrow Transplantation advance online publication, 4 February 2013; doi:10.1038/bmt.2013.4.
Bone marrow transplantation 02/2013; · 3.00 Impact Factor
-
A Tsuboi,
Y Oka, T Kyo,
Y Katayama,
O A Elisseeva,
M Kawakami,
S Nishida,
S Morimoto,
A Murao,
H Nakajima,
N Hosen,
Y Oji,
H Sugiyama
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 12/2011; 26(6):1410-3. · 8.30 Impact Factor
-
S Kako,
S Morita,
H Sakamaki,
H Ogawa,
T Fukuda,
S Takahashi,
H Kanamori,
M Onizuka,
K Iwato,
R Suzuki,
Y Atsuta, T Kyo,
T Sakura,
I Jinnai,
J Takeuchi,
Y Miyazaki,
S Miyawaki,
K Ohnishi,
T Naoe,
Y Kanda
[show abstract]
[hide abstract]
ABSTRACT: Clinical studies using genetic randomization cannot accurately answer whether adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) who have a human leukocyte antigen (HLA)-matched sibling should undergo allogeneic hematopoietic stem cell transplantation (HSCT) or chemotherapy in first remission, as, in these studies, patients without a sibling donor undergo alternative donor transplantation or chemotherapy alone after a relapse. Therefore, we performed a decision analysis to identify the optimal strategy in this setting. Transition probabilities and utilities were estimated from prospective studies of the Japan Adult Leukemia Study Group, the database of the Japan Society for Hematopoietic Cell Transplantation and the literature. The primary outcome measure was the 10-year survival probability with or without quality of life (QOL) adjustments. Subgroup analyses were performed according to risk stratification on the basis of white blood cell count and cytogenetics, and according to age stratification. In analyses without QOL adjustments, allogeneic HSCT in first remission was superior in the whole population (48.3 vs 32.6%) and in all subgroups. With QOL adjustments, a similar tendency was conserved (44.9 vs 31.7% in the whole population). To improve the probability of long-term survival, allogeneic HSCT in first remission is recommended for patients who have an HLA-matched sibling.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 11/2010; 25(2):259-65. · 8.30 Impact Factor
-
K Nakase,
K Kita,
H Miwa,
K Nishii,
M Shikami,
I Tanaka,
H Tsutani,
T Ueda,
K Nasu, T Kyo,
H Dohy,
H Shiku,
N Katayama
[show abstract]
[hide abstract]
ABSTRACT: We quantitatively assessed the expression of cytokine receptors (interleukin-2 receptor (IL-2R), IL-3R, IL-4R, IL-5R, IL-6R, IL-7R, granulocyte-macrophage colony-stimulating factor R (GM-CSFR), G-CSFR, c-fms, c-mpl, c-kit and FLT3) in cells from 211 adults with acute lymphoblastic leukemia (ALL) by flow cytometry and determined their prevalence and clinical significance. Although all cytokine receptors were expressed to various degrees, the levels of IL-3R alpha-chain (IL-3Ralpha), IL-2Ralpha, IL-2Rbeta, IL-7Ralpha, common-Rgamma(gammac), c-mpl, c-kit and FLT3 exhibited a wide spectrum > or =2000 sites/cell. Among them, IL-3Ralpha, IL-2Ralpha and FLT3 were highly expressed in B-lineage ALL, whereas IL-7Ralpha, gammac and c-kit predominated in T-lineage ALL. Higher levels of IL-3Ralpha, IL-2Ralpha, c-kit and FLT3 correlated with the expression of CD13/33. Increased IL-2Ralpha levels related to the presence of Philadelphia chromosome (Ph), leukocytosis and shorter event-free survival (EFS). C-kit preferred in male. Elevated FLT3 levels correlated with age > or =60 years. Multivariate analysis in B-lineage ALL revealed only IL-2Ralpha (P=0.028) and Ph (P=0.020) as independent factors for EFS. These findings suggest that several cytokine receptors associated with certain cellular and clinical features, but IL-2Ralpha solely had a prognostic value and should be considered as a major prognostic factor for adult ALL that is comparable with Ph.
Leukemia 03/2007; 21(2):326-32. · 9.56 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: AML1/RUNX1 mutations have been reported frequently in myelodysplastic syndrome (MDS) patients, especially those diagnosed with refractory anemia with excess blast (RAEB), RAEB in transformation (RAEBt), or AML following MDS (these categories are defined as MDS/AML). Although AML1 mutations are suspected to play a pivotal role in the development of MDS/AML, acquisition of additional genetic alterations is also necessary. We analyzed gene alterations in MDS/AML patients with AML1 mutations, comparing them to alterations in those without an AML1 mutation. AML1 mutations were significantly associated with -7/7q-, whereas MDS/AML patients without AML1 mutations showed a high frequency of -5/5q- and a complex karyotype. Patients with AML1 mutations showed more mutations of their FLT3, N-RAS, PTPN11, and NF1 genes, resulting in a significantly higher mutation frequency for receptor tyrosine kinase (RTK)-RAS signaling pathways in AML1-mutated MDS/AML patients compared to AML1-wild-type MDS/AML patients (38% versus 6.3%, P < 0.0001). Conversely, p53 mutations were detected only in patients without AML1 mutations. Furthermore, blast cells of the AML1-mutated patients expressing surface c-KIT, and SHP-2 mutants contributed to prolonged and enhanced extracellular signal-regulated kinase activation following stem cell factor stimulation. Our results suggest that MDS/AML arising from AML1/RUNX1 mutations has a significant association with -7/7q- alteration, and frequently involves RTK-RAS signaling pathway activation.
Leukemia 04/2006; 20(4):635-44. · 9.56 Impact Factor
-
A Hiramatsu,
H Miwa,
M Shikami,
T Ikai,
E Tajima,
H Yamamoto,
N Imai,
A Hattori, T Kyo,
M Watarai,
K Miura,
A Satoh,
M Itoh,
A Imamura,
H Mihara,
Y Katoh,
M Nitta
[show abstract]
[hide abstract]
ABSTRACT: Various angiogenic factors, such as vascular endothelial growth factor (VEGF) and an associated molecule, placenta growth factor (PlGF), are thought to be important for normal and malignant hematopoiesis. This study examined mRNA expression of VEGF, PlGF and receptors for these molecules in AML cells and identified the disease-specific patterns of expression. AML M3 having t(15;17) abnormality showed highest expression of VEGF and VEGF receptor type 1 (VEGFR1), suggesting the autocrine pathway of VEGF-VEGFR1. Then, t(8;21) AML demonstrated augmented expression of VEGF and VEGF receptor type 2 (VEGFR2), suggesting VEGF-VEGFR2 autocrine pathway. Then, addition of VEGFR2 kinase inhibitor in Kasumi-1, a t(8;21) AML cell line, resulted in marked inhibition of cell growth, although growth inhibitory effect of R2 kinase inhibitor to HL-60 was marginal. In addition, cell cycle analysis study showed S-phase cell population reduction by R2 kinase inhibitor in Kasumi-1, but not in HL-60. This observation is thought to be the rationale for novel molecular target therapy directed to angiogenic molecules.
Leukemia and Lymphoma 02/2006; 47(1):89-95. · 2.58 Impact Factor
-
K Nishii,
E Usui,
N Katayama,
F Lorenzo,
K Nakase,
T Kobayashi,
H Miwa,
M Mizutani,
I Tanaka,
K Nasu,
H Dohy, T Kyo,
M Taniwaki,
T Ueda,
K Kita,
H Shiku
[show abstract]
[hide abstract]
ABSTRACT: t(8;21)(q22;q22) is the most frequently observed karyotypic abnormality associated with acute myeloid leukemia (AML), especially in FAB M2. Clinically, this type of AML often shows eosinophilia and has a high complete remission rate with conventional chemotherapy. t(8;21) AML is also frequently associated with additional karyotypic aberrations, such as a loss of the sex chromosome; however, it is unclear whether these aberrations change the biological and clinical characteristics of t(8;21) AML. To investigate this issue, 94 patients with t(8;21) AML were categorized according to their additional karyotypic aberrations, which were detected in more than three cases, and then morphologic features, phenotypes, expression of cytokine receptors, and clinical features were compared to t(8;21) AML without other additional aberrant karyotypes. t(8;21) AML with loss of the sex chromosome and abnormality of chromosome 9 were found in 27 cases (29.3%) and 10 cases (10.6%), respectively; however, no differences were observed from the t(8;21) AML without other additional karyotypes in terms of morphological and phenotypic features. There was also no significant difference in the clinical outcome among these three groups. On the other hand, trisomy 4 was found in three cases (3.2%) and these cells showed low expressions of CD19 (P=0.06) and IL-7 receptor (P=0.05), and high expressions of CD33 (P=0.13), CD18 (P=0.03), and CD56 (P=0.03) when compared to t(8;21) AML without additional karyotypes. Moreover, all three t(8;21) AML cases with trisomy 4 did not show eosinophilia in their bone marrow and died within 2.4 years. These observations suggest that additional karyotypic aberration, t(8;21) with trisomy 4 is rare, but it may constitute a distinctive subtype of t(8;21) AML.
Leukemia 05/2003; 17(4):731-7. · 9.56 Impact Factor
-
K Nishii,
N Katayama,
H Miwa,
M Shikami,
E Usui,
M Masuya,
H Araki,
F Lorenzo,
T Ogawa, T Kyo,
K Nasu,
H Shiku,
K Kita
[show abstract]
[hide abstract]
ABSTRACT: Ikaros, a zinc finger transcription factor, is essential for lymphoid development. Mutant mice expressing dominant-negative Ikaros gene (Ikaros) isoforms develop an aggressive form of lymphoid malignancies. We examined the expression of Ikaros isoforms in 11 leukemic cell lines and adult acute lymphoblastic leukemia cells from 36 patients with B-precursor acute lymphoblastic leukemia (pre-B ALL) and nine with T-precursor acute lymphoblastic leukemia (pre-T ALL), using reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. In one pre-B ALL cell line, INC cells, and primary leukemic cells from 16 patients with pre-B ALL, we found the predominant expression of a non-DNA-binding Ikaros isoform, Ik-6. However, Ik-6 was not detected in pre-T ALL cells. All of pre-B ALL cells expressing Ik-6 were CD10(+), whereas CD10(-) pre-B ALL cells did not express Ik-6. The expression of Ik-6 was not related to karyotype abnormalities such as t(9;22) and t(4;11). Proteins from the cells that expressed Ik-6 alone failed to bind to the Ikaros protein-specific binding sequence in DNA. Ikaros proteins lacking the DNA binding sequences were detected in the cytoplasm but not in the nucleus of the cells. When INC and primary pre-B ALL cells that express Ik-6 alone were irradiated and cultured in the absence of serum, these cells produced functional Ikaros isoforms, Ik-1 and Ik-2. Purified CD19(+) CD10(-) and CD19(+) CD10(+) cells from normal human bone marrow did not express Ik-6. The predominant expression of Ik-6, which is the result of post-transcription dysregulation, is characteristic of adult pre-B ALL, especially CD10(+) pre-B ALL.
Leukemia 08/2002; 16(7):1285-92. · 9.56 Impact Factor
-
J Takeuchi, T Kyo,
K Naito,
H Sao,
M Takahashi,
S Miyawaki,
K Kuriyama,
S Ohtake,
F Yagasaki,
H Murakami, [......],
M Nishimura,
K Shinagawa,
T Fukushima,
H Taguchi,
T Morii,
S Mizuta,
H Akiyama,
Y Nakamura,
T Ohshima,
R Ohno
[show abstract]
[hide abstract]
ABSTRACT: In order to improve the disappointing prognosis of adult patients with acute lymphoblastic leukemia (ALL), we applied similar induction therapy as that used for acute myeloid leukemia (AML), ie frequent administration of doxorubicin (DOX). DOX 30 mg/m(2) was administered from days 1 to 3 and from days 8 to 10 together with vincristine, prednisolone, cyclophosphamide and L-asparaginase, followed by three courses of consolidation and four courses of intensification. From December 1993 to February 1997, 285 untreated adult patients with de novo ALL were entered. Of 263 evaluable patients (age 15 to 59; median 31), 205 (78%) obtained complete remission (CR). At a median follow-up period of 63 months, the predicted 6-year overall survival (OS) rate of all patients was 33%, and disease-free survival (DFS) rate of CR patients was 30%, respectively. By multivariate analysis, favorable prognostic factors for the achievement of CR were age <40 and WBC <50 000/microl; for longer OS were age <30 and WBC <30 000/microl; and for longer DFS of CR patients were FAB L1 and ALT <50 IU/l. Among 229 patients who had adequate cytogenetic data, 51 (22%) had Philadelphia (Ph) chromosome. Ph-negative chromosome was a common favorable prognostic factor for CR, longer OS and DFS. DFS was not different between early sequential intensification (n = 48) and intermittent intensification (n = 43) during the maintenance phase. Among CR patients under 40 years old, the 6-year survival was not different between the allocated related allo-BMT group (34 patients) and the allocated chemotherapy group (108 patients). However, among patients with Ph-positive ALL, the survival of patients who actually received allo-BMT was superior to that of patients who received chemotherapy (P = 0.046).
Leukemia 07/2002; 16(7):1259-66. · 9.56 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Genetic alterations, including microsatellite instability (MSI), are ultimate steps toward malignant process. To investigate MSI in A-bomb survivors, leukaemic cells were analysed from 13 acute myelocytic leukaemia patients with a history of radiation exposure and also in 12 de novo patients.
To assess the microsatellite changes, a fluorescent system in 10 loci (BAT40, D3S643, D5S107, IRF1, MYC, D9S171, WT1, TP53, DM, D17S855) was used.
MSI analysis revealed a high frequency of multiple microsatellite changes in the exposed patients (84.6%) compared with non-exposed patients (8.3%). There was a significant difference (p < 0.001) between the two groups.
These analyses clearly demonstrate that leukaemic cells from heavily exposed patients contain a number of genetic instabilities that may strongly influence the development of leukaemia among people exposed to the Hiroshima A-bomb radiation.
International Journal of Radiation Biology 06/2001; 77(6):687-94. · 2.28 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To investigate the relationship between the pattern of methylation at the major breakpoint cluster region (M-BCR) and transformation of chronic myelocytic leukemia (CML) from the chronic to the blastic phase, the M-BCR methylation status was examined serially from chronic to blastic phase in 23 CML patients. The DNA of mononuclear cells from bone marrow or peripheral blood was digested with restriction enzymes HpaII and BglII, and hybridized with a 5'M-BCR probe. The methylation status was stable during evolution of CML from chronic to the myeloid blastic phase. Cells in both phases showed consistent methylation patterns consisting of fully methylated rearranged fragments of variable size, 4.8, 3.1/3.0, and 2.7/2.5 kb. Conversely, there was substantial heterogeneity in methylation patterns in patients with lymphoid crisis. All lymphoid-crisis patients studied in blastic phase showed a pattern distinct from that of the chronic phase in the same patient, as well as from the myeloid pattern, suggesting cell lineage-specific M-BCR methylation. Moreover, in four of six patients with lymphoid crisis, the chronic-phase patterns were different from those of cases with myeloid crisis. Ph-positive and -negative acute lymphocytic leukemia (ALL) showed methylation patterns different from those of lymphoid crisis in CML. Although the number of patients with lymphoid crisis studied has been limited, these results suggest that analysis of M-BCR methylation status may be of clinical use in distinguishing lymphoid from myeloid crises and predicting the cell lineage of a crisis when the disease is still in the chronic phase.
Cancer Genetics and Cytogenetics 05/2001; 126(2):102-10. · 1.39 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We examined the expression of hybrid phenotype in 236 adults with acute lymphoblastic leukemia (ALL; 188 B-lineage ALL and 48 T-lineage ALL). In B-lineage ALL, myeloid antigen (mAg) CD15 was concentrated in CD10-CD20- cases (49%); CD13 (42%); and CD33 (43%) in CD10+CD20- cases. This trend had no correlation with the presence of Ph1 or t(4;11) chromosomal abnormality. T-cell antigen CD2, CD4, and CD7 was seen in four, four, and two cases, respectively, and CD4+ and CD7+ cases commonly expressed CD13 and/or CD33 (CD13/CD33). In T-lineage ALL, expression of mAg, CD11b (47%), CD13 (38%), CD15 (28%), and CD33 (51%) was restricted to CD3- cases. B-cell antigen CD19 was found in two cases with CD7 solely as T-cell antigen, and these cases possessed CD13/CD33. CD21 was detected in three cases with CD3. In whole ALL, CD13/CD33 was associated closely with the presence of stem-cell antigen CD34, and in T-lineage ALL, CD13/CD33 had a significant correlation with additional stem-cell features, such as HLA-DR, multidrug resistance 1 (MDR1) and c-kit gene expression. Our results suggest that immature ALL cells frequently express B+M+, T+M+, and occasionally B+T+M+ phenotype; that B+T+M- phenotype is extremely rare; and that mAg expression in B-lineage ALL is complicated as compared to T-lineage ALL.
Cancer Detection and Prevention 02/2001; 25(4):394-405. · 2.52 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We analyzed 32 patients with various hematological malignancies including acute myelocytic leukemia and non-Hodgkin lymphoma with a breakpoint at 11q22-q25 of chromosome 11, but who did not have rearrangements of the MLL/ALL-1 gene. The breakpoint in each patient was identified by fluorescence in situ hybridization using 21 cosmid probes and 2 YAC probes. Breakpoints for each "rearrangement" involving translocations such as t(1;11), t(2;11), inv(11), t(11;15), and t(10;11) found in 5 of the 11 patients had breakpoints in a small region from Ccl11-430 to Ccl11-526 at 11q22-q23.1. Furthermore, breakpoints for chromosome deletions at 11q21-q23 in 10 patients were located in the same region as that of translocations. A commonly deleted region among 8 patients was identified from Ccl11-526 to Ccl11-555 at 11q23.1. Fluorescence in situ hybridization analysis revealed that breakpoints for additive chromosome [add(11)] aberrations, which had additional material of unknown origin at 11q23 to 11q25 in 11 patients, were not located at 11q23 but rather at the more telomeric site of Ccl11-503 to VIJ(2)2072 at 11q25. These results indicated that the patients had several restricted breakpoint sites, which means that these chromosomal regions have recurrent oncogenes and tumor suppressor genes for pathogenesis for leukemia and lymphoma.
Cancer Genetics and Cytogenetics 02/2001; 124(1):27-35. · 1.39 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We report the characterization of a rare chromosomal translocation, a t(2;11)(q31;p15), which occurred in a patient with de novo acute myeloid leukemia (AML-M4). By 3'-RACE and RT-PCR analyses, two kinds of NUP98-HOXD13 fusion transcript were detected. In addition, we identified a novel fusion transcript, NUP98-FN1, in the same patient. Ectopic expression of the wild-type HOXD13 gene was also observed in the patient, suggesting that HOXD13 contributes to the development of this type of leukemia. The NUP98-HOXD13 fusion transcript was predicted to encode a 552 or 569-amino acid protein containing the Phe-Gly (FG) repeat region of NUP98 and the homeodomain of HOXD13. The NUP98-FN1 fusion transcript was predicted to encode a 482 or 499-amino acid protein consisting of the same N-terminal region of NUP98 and a C-terminal region of 12 amino acids derived from a previously unidentified sequence. We isolated and characterized the chromosomal breakpoints. The breakpoint at 11p15 is mapped within a LINE repetitive element in a 9 kb intron of NUP98, and more than 60% of the sequenced 3 kb region surrounding the breakpoint junction consists of repetitive elements. The other breakpoint at 2q31 is in an intron of FN1, which is located 7 kb upstream of HOXD13, and the repetitive sequence content of the breakpoint junction is low. Local sequence duplications at genomic breakpoints suggest that the t(2;11) translocation is mediated through staggered double-strand DNA breaks. These results throw light on the mechanisms responsible for the generation of t(2;11) translocation and on the processes leading to t(2;11) leukemia.
Leukemia 10/2000; 14(9):1621-9. · 9.56 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Thirty-six patients with chronic myelocytic leukemia (CML) in the blastic phase were examined by fluorescence in situ hybridization to clarify the mechanisms of progression of the disease. Two of 19 CML patients in the blastic phase (10.5%) had an extra fused BCR-ABL gene on structurally complex chromosome aberrations in addition to the Ph chromosome. Another patient had an extra ABL oncogene on the end of a deleted chromosome, resulting in three copies of the ABL oncogene. These three patients showed additional chromosome aberrations, such as der(12), der(15), and der(18), which differ from the standard karyotypic evolution in the blastic phase. Amplification of the fused BCR-ABL gene or the ABL oncogene seemed to be induced by transposition. These segmental transpositions suggest that these regions have high genetic instability possibly leading to blastic transformation.
Cancer Genetics and Cytogenetics 06/2000; 119(1):8-14. · 1.39 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Fluorescence in situ hybridization (FISH) is suitable for detecting different types of chromosome aberrations on interphase nuclei even in specimens with no or few chromosome metaphases. However, it is not known why FISH is superior to conventional G-banding analysis. The sensitivity of interphase FISH was compared to that of G-banding analysis in 288 leukemia/lymphoma patients for 10 different types of chromosome aberrations: t(9;22) (M- and m-BCR), t(8;21), 11q23 abnormalities, t(15;17), del(5)/-5, del(13)/-13, +8, -7, and +12. The results revealed that t(15;17) positive cells could not proliferate well in culture, leading to underestimation of abnormality by G-banding. Monosomy 7 in acute myelocytic leukemia (AML) and myelodysplastic syndrome (MDS) as well as trisomy 12 and deletion chromosome 13 in chronic lymphocytic leukemias (CLL) were also severely underestimated by G-banding. On the other hand, no discrepancies were observed in t(8;21), t(9;22), translations involving 11q23, or in trisomy 8. These findings indicate the superiority of interphase FISH over conventional cytogenetics for detecting chromosome abnormalities in small clones, especially for monosomy 7 or (15;17) translocations.
Cancer Genetics and Cytogenetics 12/1999; 115(1):32-8. · 1.39 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In order to identify a commonly deleted region of 13q14 on chromosome 13, we performed fluorescence in situ hybridization (FISH) on 17 patients with myeloid malignancies and 12 patients with lymphoid leukemia/lymphoma who exhibited either deletion or translocation at 13q14. Three cosmid probes (RB, D13S319 and D13S25) hybridizing to sequences on 13q14 were used. Fourteen of the 17 patients with myeloid malignancies (82.4%) exhibited allelic loss at the RB, D13S319 and D13S25 locus, whereas only three of the 12 patients with lymphoid malignancies (25.0%) exhibited loss within these loci. These three patients had chronic lymphocytic leukemia (CLL). Six, two and one of the remaining nine lymphoid leukemia/lymphoma patients had breakpoints centromeric to the RB gene, telomeric to D13S25 and within the D13S319 locus, respectively. A high frequency of allelic loss was found using these probes in patients with myeloid malignancies, compared to in patients with leukemia in the lymphoid origin, except CLL patients. These results indicate that loss of the RB gene itself or a region between RB and D13S319, which includes commonly deleted loci, may play an important role in myeloid leukemogenesis.
Leukemia 10/1999; 13(9):1367-73. · 9.56 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To detect a translocation (8;21)(q22;q22) in interphase cells by fluorescence in situ hybridization (FISH), we investigated three probe combinations: single-color hybridization with two cosmid probes (cY8 and cY3), single-color hybridization with four cosmid probes (cY8, cY3, cY107, and cYR4), and dual-color hybridization with two cosmid probes (cY107 and cYR4) from the AML1 gene flanking or overlapping the breakpoint region. Over 95% of nuclei gave sufficient signals in all three probe combinations, and the detection rates were not statistically different among them. Among 18 patients examined at diagnosis, 12 with t(8;21) were also monitored for the number of residual leukemic cells after chemotherapy or bone marrow transplantation (BMT). There were some discrepancies between morphology and genetic (especially FISH) results at partial, or even complete remission. As leukemic cells with t(8;21) can maturate, morphological assessment alone is insufficient to evaluate the residual leukemic cells. Interphase FISH provided more precise information about the clinical status of patients with an 8;21 translocation after treatment.
Cancer Genetics and Cytogenetics 09/1999; 113(1):29-35. · 1.39 Impact Factor
-
M Shikami,
H Miwa,
K Nishii,
T Takahashi,
H Shiku,
H Tsutani,
K Oka,
H Hamaguchi, T Kyo,
K Tanaka,
N Kamada,
K Kita
[show abstract]
[hide abstract]
ABSTRACT: We report the cellular characteristics of cells from three patients with de novo acute myelocytic leukaemia (AML) with t(16;21)(p11;q22), two M4 and one M5a according to the FAB classification, and two permanent cell lines with t(16;21)(p11;q22), TSU1621MT and YNH-1. The FUS/ERG fusion mRNA was demonstrated in all cases by reverse transcriptase-polymerase chain reaction (RT-PCR). The immunophenotypes of the AML cells, and YNH-1 and TSU1621MT cell lines with t(16;21) were characterized as CD34+CD33+CD13+CD11b+CD18+CD56+ HLA-DR-/+. Cells from all samples strongly expressed c-kit, granulocyte colony-stimulating factor receptor (G-CSFR), c-fms (macrophage colony-stimulating factor receptor), interleukin-3 receptor alpha chain (IL-3Ralpha), and granulocyte macrophage colony-stimulating factor receptor alpha chain (GM-CSFRalpha), and these data corresponded well to the growth responsiveness to the cytokines. IL-2Ralpha expression was also found in all t(16;21) samples, but IL-2 did not act on the proliferation of the leukaemic cells in in vitro cultures. G-CSF distinctly promoted the proliferation of leukaemic cells of t(16;21) AML, but did not enhance the expression of MPO and neutrophil differentiation of these cells. Our findings indicate that AML cells with t(16;21) preserve stem cell properties such as CD34 and c-kit expression, and suggest that they have the potential to differentiate into a monocytic lineage. The relationship between the unique cellular characteristics (especially CD56 and IL-2Ralpha expression) and FUS/ERG protein remains undetermined.
British Journal of Haematology 07/1999; 105(3):711-9. · 4.94 Impact Factor
-
M Tanimoto,
S Miyawaki,
T Ino, T Kyo,
H Sakamaki,
T Naoe,
A Hiraoka,
N Asou,
T Ohshima,
K Tsubaki, [......],
T Ueda,
S Minamil,
K Okabe,
H Saito,
H Murakami,
M Hirano,
H Dohy,
Y Onozawa,
H Suzuki,
R Ohno
[show abstract]
[hide abstract]
ABSTRACT: The Japan Adult Leukemia Study Group conducted the ALL-87 study to determine whether response-oriented induction therapy and intensive consolidation and maintenance/intensification therapies could increase complete remission (CR) rate and survival in adult acute lymphoblastic leukemia (ALL). Of 121 patients registered, 116 were evaluated. Patients' ages ranged from 15 to 72 years (median, 38 years). Induction therapy, which consisted of doxorubicin, vincristine, cyclophosphamide, L-asparaginase and prednisolone, was given in a response-oriented individualized fashion. Patients were randomly allocated either to receive or not, intrathecal chemotherapy on day 8 of the induction therapy. Complete remission (CR) was obtained in 97 (83.6%) patients (90.2%) in patients of less than 50 years of age and 67.6% in patients 50 years of age or older). At a median follow-up period of 65 months, the predicted 6-year overall survival and event free survival (EFS) rates of 116 patients were 23.4 and 20.0%, respectively. Predicted 6-year survival and disease-free survival (DFS) rates of 97 CR patients were 28.2 and 24.5%, respectively. By multivariate analysis, patients under 40 years of age (P = 0.002) or those with a platelet count of more than 100,000/microliters (P = 0.004) were significant favorable prognostic factors for obtaining CR, and days to CR less than 50 (P = 0.003), patients under 50 years of age (P = 0.005) were significant favorable factors for longer DFS. There was no significant difference in CR rates and DFS between the two randomized groups according to the intrathecal chemotherapy on day 8. Response-oriented induction therapy produced a high CR rate, but fairly intensive consolidation and maintenance/intensification chemotherapies resulted in only a marginal effect on DFS in adult ALL. Although age is one of the most important prognostic factors in ALL, the outcome was unsatisfactory even in younger adult patients using chemotherapeutic regimen employed in this study.
International Journal of Hematology 01/1999; 68(4):421-9. · 1.27 Impact Factor
