Ming-Chi Liu

Distinct clinical and biologic characteristics in adult acute myeloid leukemia bearing the isocitrate dehydrogenase 1 mutation

Mutations of nicotinamide adenine dinucleotide phosphate-dependent isocitrate dehydrogenase gene (IDH1) have been identified in patients with gliomas. Recent genome-wide screening also revealed IDH1 mutation as a recurrent event in acute myeloid leukemia (AML), but its clinical implications in AML are largely unknown. We analyzed 493 adult Chinese AML patients in Taiwan and found 27 patients (5.5%) harboring this mutation. IDH1 mutation was strongly associated with normal karyotype (8.4%, P = .002), isolated monosomy 8 (P = .043), NPM1 mutation (P < .001), and French-American-British M1 subtype (P < .001), but inversely associated with French-American-British M4 subtype (P = .030) and expression of HLA-DR, CD13, and CD14 (P = .002, .003, and .038, respectively). There was no impact of this mutation on patient survival. Sequential analysis of IDH1 mutation was performed in 130 patients during follow-ups. None of the 112 patients without IDH1 mutation at diagnosis acquired this mutation at relapse. In all 18 IDH1-mutated patients studied, the mutation disappeared in complete remission; the same mutation reappeared in all 11 samples obtained at relapse. We conclude that IDH1 is associated with distinct clinical and biologic characteristics and seems to be very stable during disease evolution.

Methylation of the p15INK4B gene in myelodysplastic syndrome: it can be detected early at diagnosis or during disease progression and is highly associated with leukaemic transformation

To investigate the time sequence of occurrence of p15INK4B gene methylation in myelodysplastic syndrome (MDS) and its correlation with leukaemic transformation and survival of patients, the methylation status of the p15INK4B promoter region was analysed in 50 patients and was serially studied in 22 of them. Of the 50 patients, 17 (34%) showed p15INK4B gene methylation, first demonstrated at diagnosis or during follow‐up. When FAB subtypes at the time of study were used in the analysis, the incidence of p15INK4B methylation in each risk group of MDS remained stable throughout the course: 0% for low‐risk MDS [refractory anaemia (RA) and RA with ring sideroblasts] and from 23% at diagnosis to 30% for high‐risk MDS [RA with excess of blasts (RAEB), RAEB in transformation and chronic myelomonocytic leukaemia] respectively. The incidence of p15INK4B methylation rose to 60% at initial study and, finally, to 75% in cases of acute myeloid leukaemia (AML) evolved from MDS. Most patients (69%) with p15INK4B methylation showed disease progression to AML; it could be detected before, at the time or after the diagnosis of leukaemic transformation. p15INK4B methylation in MDS patients implicated a shorter survival time in univariate analyses, but its prognostic significance disappeared in multivariate analyses. In conclusion, p15INK4B methylation can be detected early at the diagnosis of MDS or acquired during disease progression. It may play an important role in the pathogenesis of some high‐risk MDS and is related to leukaemic transformation of MDS.

Clonal chromosomal abnormalities as direct evidence for clonality in nasal T/natural killer cell lymphomas

Nasal T/natural killer (NK) cell lymphoma is a distinct clinicopathologic entity which is more prevalent in Asia than in America and Europe. The clonal nature of the infiltrating lymphoid cells is difficult to demonstrate because of the lack of immunologic markers for clonality and the absence of clonal T‐cell receptor gene rearrangement in most cases. In this study, clonal chromosomal abnormalities were detected in the tumour cells from four patients with nasal T/NK cell lymphoma. This finding provided direct evidence for clonality of the disease. Moreover, nonrandom cytogenetic abnormalities, including isochromosome for the short arm (p) of chromosome 6, isochromosome for the long arm (q) of chromosome 1, partial deletion of 6q, and aberrations at 11q, were disclosed. Isochromosome 6p was the sole structural abnormality in one patient, which may be a pathognomonic change in nasal lymphoma.

Cytogenetic study of acute lymphoblastic leukemia and its correlation with immunophenotype and genotype

Among 72 Chinese patients with acute lymphoblastic leukemia (ALL), 50 had clonal chromosomal abnormalities. Structural abnormalities were detected in 42 patients: these included t(9;22) in 9, t(1;19) in 6, t(4;11) in 5, del(11)(q23) in 4, and del(6q) in 4. Adults had a higher incidence of t(9;22) and t(1;19) but a lower incidence of t(4;11) and hyperdiploid greater than 50 karyotype than children. A significant difference was also noted in white blood cell (WBC) count among various karyotypic groups. Patients with chromosomal abnormalities t(9;22), t(1;19), t(4;11) and del(11) (q23) had a shorter complete remission duration as compared with patients free of these abnormalities. Immunophenotyping was performed on 69 patients. All patients with t(9;22), t(1;19), and t(4;11) had B-lineage ALL restricted to certain stages of maturation: groups III and IV, groups IV and V, and group II, respectively (according to the classification of Foon and Tood). Among patients with t(9;22), t(4;11), and del(11)(q23), which have been considered to be associated with acute mixed-lineage leukemia, one each, respectively, showed myeloid antigen expression on the leukemic blasts (My+ ALL). No cross-lineage rearrangements of immunoglobulin (Ig) or T-cell receptor (TCR) genes were detected in these karyotypic subgroups of patients who underwent gene analysis.

Acute leukemic transformation of myelodysplastic syndrome—Immunophenotypic, genotypic, and cytogenetic studies

The clinical and biological characteristics of myelodysplastic syndrome (MDS) in acute leukemic transformation were studied in 23 patients. All had myeloid transformation according to FAB criteria, but coexpression of lymphoid-associated antigens was detected in five of the 20 patients who underwent an immunophenotypic study. Rearrangement of the immunoglobulin heavy chain gene was also observed in one of the five patients who coexpressed lymphoid markers and that of the T-cell receptor beta chain gene in another one. None had pure lymphoid transformation. Clonal chromosomal abnormalities were noted in 12 (63%) of the 19 patients who underwent cytogenetic study, most commonly - 7 (six patients or 32%). In the 18 patients who underwent serial analyses both at MDS diagnosis and at acute transformation, seven (39%) underwent karyotypic evolution. The most common new or additional aberrations were +8 and +21. N-ras gene mutation was detected in two of the nine patients at acute leukemic transformation. The median interval from diagnosis of MDS to onset of acute transformation was 10 months (1-36 months). Patients with a normal karyotype at diagnosis had a significantly longer chronic phase duration than those with chromosomal abnormalities (median of 20 months vs. 5 months). However, all had a short survival time after diagnosis of acute leukemia, whether chromosomal anomalies were present or not.

Cytogenetic characterization of Epstein-Barr virus-associated T-cell malignancies

Recently, Epstein-Barr virus (EBV) infection has been found not only to be associated with Burkitt lymphoma and nasopharyngeal carcinoma but also with some T-cell malignancies. Cytogenetic studies were performed on four Chinese patients with EBV-associated T-cell neoplasms: three peripheral T-cell lymphomas and one large granular lymphocyte leukemia with coexpression of T-cell antigen. Clonal chromosomal abnormalities were detected in all four patients. Rearrangements of chromosome 7 were observed in three patients: one at 7p22, one at 7q35 or 36, and the remaining one at both sites. The last patient also had a chromosomal abnormality involving 14q11. Trisomy of part of the 1q segment was detected in two patients. The results revealed that the chromosomal abnormalities in these patients were similar to those observed in other T-cell lymphomas. Further studies on more patients are necessary to find out whether there are specific chromosomal aberrations in EBV-associated T-cell neoplasms.

Clonal disease of natural killer large granular lymphocytes in Taiwan

Lymphoproliferative diseases of large granular lymphocytes (LDGL) may arise from either CD3+ T cells or CD3− natural killer (NK) cells. LDGL with clonal proliferation of large granular lymphoeytes (LGL) is defined as LGL leukaemia. The number of patients with NK‐LGL leukaemia reported is limited and the pathogenesis of the disease is not yet clear. From 1991 to 1998 six patients with cytogenetically proved clonal disease of NK‐LGL were identified in our institute. All were seropositive for Epstein‐Barr virus (EBV). EBV RNA or DNA could be detected in LGL from four patients by EBV in situ hybridization or Southern blot analysis. Most patients ran an aggressive clinical course and five died of the disease. Nonrandom clonal chromosomal abnormalities, including duplication of 1q, rearrangement at 3q and loss of chromosomes Y, 13 or 10, were noted in the six patients from this study and in eight from the literature. The implications of these recurrent cytogenetic aberrations in the development and progression of the disease deserve further studies.