Yongquan Xue

Specific chromosomal translocations and therapy-related leukemia induced by bimolane therapy for psoriasis.

This paper reports for the first time results of cytogenetic studies on 14 consecutive secondary acute non-lymphocytic leukemia (S-ANLL) induced by bimolane therapy. They included 10 males and 4 females with ages ranging from 17 to 54 years. They had all suffered from psoriasis and received bimolane treatment before the occurrence of their leukemia. The total dose of bimolane ranged from 40 to 400 g (mean dose 194 g). The interval between the initiation of bimolane therapy and the diagnosis of leukemia was 12-96 months (median 30 months). A preleukemic phase was only found in one case. No dysplastic features in the hemopoietic series were seen in any patient. Chromosome analysis of bone marrow cells using banding techniques revealed clonal karyotypic abnormalities in all cases: t(15;17) in 8 cases of M3, of which 75% had extra abnormalities, t(8;21) in 4 cases of M2, del(7q) only in one case of M4 and one case of M5. After antileukemic therapy, complete remission was obtained in 10 out of 12 cases with specific translocations and one out of 2 cases with 7q-anomaly, respectively. The former survived 4-58 months (median 12 months), while the latter 1 and 9 months, respectively. This study indicates that: (1) bimolane is a causative factor of leukemia in this series; (2) the leukemia in our series is therapy-related leukemia (TRL) rather than de novo ANLL; (3) there exists, in fact, a new subgroup of TRL characterized by specific rearrangements, whose clinical, hematological and prognostic features and pathogenetic mechanism may be different from classical TRL characterized by chromosome abnormalities involving absence or deletion of parts of chromosome 5 and/or 7.

Clinical and molecular cytogenetic studies in seven patients with myeloid diseases characterized by i(20q

We report on seven patients with myeloid diseases characterized by i(20q−) anomaly. Four patients were male and three were female, their median age was 57 years. The diagnosis at presentation was myelodysplastic syndrome in six patients, acute myeloid leukaemia in one patient. Four died but three survived and remain anaemic. The survivals were 6 months for patient 1, 7 months for patient 2, 17 d for patient 4 and 28 d for patient 5. Chromosome specimens were prepared by direct and/or short‐term culture of bone marrow cells. Karyotype analysis was performed by R‐ and G‐banding technique, which showed that one of the normal chromosomes 20 was substituted by one or two small metacentric chromosomes in all seven patients. The karyotype was ider(20)(q10)del(20)(q11q13), i.e. i(20q−) in six patients by dual‐colour fluorescence in situ hybridization assay using two probes (a subtelomeric probe for 20q and an unique probe for 20q12). As far as we know, this anomaly has not been reported previously. Thus, we consider that i(20q−) is a novel and rare recurrent chromosomal abnormality that is specifically associated with myeloid diseases and may indicate a poor prognosis.

Interphase fluorescence in situ hybridization detection of cytogenetic abnormalities in B-cell chronic lymphocytic leukemia.

The most frequent chromosomal abnormalities in B-cell chronic lymphocytic leukemia (B-CLL) are deletions on 13q14 and 17p13, trisomy 12, and 14q32 rearrangement. Conventional cytogenetic analysis underestimates the frequency of specific chromosome aberrations in B-CLL because of the low rate of spontaneous mitoses and the poor response to mitogen stimulation. We used interphase fluorescence in situ hybridization (I-FISH) to explore the incidence of chromosomal changes in the peripheral blood cells of B-CLL patients. Probes for 13q14 (D13S319), 17p13 (p53), the centromere of chromosome 12 (CEP12), and 14q32 (IGHC/IGHV) were applied to detect chromosomal aberrations in peripheral blood samples from 83 B-CLL patients (60 men, 23 women). Molecular cytogenetic aberrations were found in 61 cases (73.5%), and 8 patients (9.6%) showed 2 kinds of abnormalities. The most frequent abnormality was deletion of 13q14 (41.0%), followed by +12 (19.3%), deletion of 17p13 (12%), and 14q32 rearrangement (9.6%). FISH results were analyzed for correlation with Binet stages. The percentages of patients who showed abnormalities by FISH were 73.0%, 73.3%, and 80% for Binet stages A, B, and C, respectively, and the percentages of patients with abnormalities who showed 2 anomalies were 7.9%, 27.3%, and 0% for Binet stages A, B, and C, respectively. We noted no consistent pattern among the various Binet stages in the distribution of either the types of FISH-detected anomalies or the numbers of FISH anomalies. I-FISH was found to be a rapid, exact, and sensitive technique for analysis of chromosome aberrations in CLL. FISH could provide accurate information regarding the molecular cytogenetic features of CLL.

A case of basophilic leukemia bearing simultaneous translocations t(8;21) and t(9;22)

We report a case of basophilic leukemia with simultaneous translocations of t(8;21) and t(9;22). The patients clinical and hematologic findings were characteristic only of t(9;22) but not of t(8;21). This unusual cytogenetic phenomenon raises a challenge to the current concepts of primary chromosomal abnormalities in cancer.

The utility of fluorescence in situ hybridization analysis in diagnosing myelodysplastic syndromes is limited to cases with karyotype failure

Fluorescence in situ hybridization (FISH) is being used increasingly in cytogenetic diagnosis of myelodysplastic syndromes (MDS). However, the utility of FISH in this role has not been well-defined. A total of 249 de novo MDS patients were submitted to karyotyping and FISH analysis for -5/del(5)(q31), -7/del(7)(q31), +8, -17/i(17)(q10), del(20)(q12), and -Y. Of the 234 patients with available karyotypic data, 143 cases (60.9%) demonstrated normal karyotype and 91 cases (39.1%) showed abnormal karyotype. FISH confirmed R-banding findings in 96.6% (226/234) of samples with successful karyotyping and detected cytogenetic abnormalities in 46.7% (7/15) of cases with karyotype failure. Of the 3.4% (8/234) patients showing discrepancies between FISH and R-banding, FISH revealed cytogenetic abnormalities in four patients with normal karyotypes and four patients with complex karyotypes. These results highlight FISH analysis has limited value in MDS cases with successful karyotyping and is only informative in MDS cases with karyotype failure.

Translocation (8;21) in oligoblastic leukemia: Is this a true myelodysplastic syndrome?

An 8;21 translocation with trisomy 4 is described in a 36-year-old Chinese woman who presented with an oligoblastic leukemia with myelodysplastic (MDS) features. Progression to acute myeloblastic leukemia (AML) occurred 3 months after presentation. She died of septicemia without remission. Through a review of the data in 10 cases of oligoblastic leukemia with t(8;21) in the literature, we make the following comments. (i) Oligoblastic leukemia with t(8;21) represents 2-3% of cases with this karyotype. (ii) Such cases behave in a similar manner to de novo AML. (iii) The presence of features of MDS has no affect on the behaviour of the disease. (iv) Such cases should be treated without delay with intensive chemotherapy.

t(8;20)(q22;p13): a novel variant translocation of t(8;21) in acute myeloblastic leukaemia

A novel variant translocation t(8;20)(q22;p13) detected by karyotype analysis of bone marrow cells using R‐ and G‐banding techniques, is reported in a case of M2‐acute myeloid leukaemia (AML). The leukaemic cells were indistinguishable morphologically from that of M2‐AML with t(8;21)translocation. RT‐PCR revealed no AML1/ETO fusion transcript, but the wild‐type ETO‐3′ was expressed in the bone marrow cells suggesting that t(8;20) is a true simple variant translocation of t(8;21), and that a fusion gene consisting of ETO and an unidentified gene located in band 20p13 may exist in our case. Further study is required to clarify the entity of the assumed fusion gene.

Analysis of NPM1 Gene Mutations in Chinese Adults with Acute Myeloid Leukemia

Many European groups have recently described that mutations at exon-12 of the nucleophosmin (NPM1) gene are the most frequent genetic lesion in patients with acute myeloid leukemia (AML), especially in the presence of a normal karyotype. This study explored the prevalence and clinical profile of NPM1 mutations in a cohort of 156 Chinese adults with AML. NPM1 exon-12 mutations were detected using direct sequencing or fragment analysis of genomic DNA polymerase chain reaction products. NPM1 mutations were present in 28.2% of the overall population, including 1/1 (100%) of M0, 11/27 (40.7%) of M1, 11/46 (23.9%) of M2,0/29 (0%) of M3,2/9 (22.2%) of M4,18/39 (46.2%) of M5, and 1/5 (20.0%) of M6. NPM1 gene mutations were more prevalent in patients with a normal karyotype (37 of 90; 41.1%) when compared with patients with karyotypic abnormalities (7 of 66; 10.6%;P <.001). Sequence analysis of 25 NPM1-mutated cases revealed known mutations (type A, D, NM, and PM) as well as one novel sequence variation (here named as type S). All mutational types were heterozygous and showed a 4 bp insertion. NPM1 mutations were significantly associated with old age (P <.05), high peripheral white blood cell count (P <.05), and the subtypes of French-American-British categories M1/M5, but negatively associated with expression of CD34 (P <.05) and CD117 (P <.05). Thus, this study provides the methods of NPM1 exon-12 mutations detection and related clinical data of NPM1 mutated cases in a Chinese population.

FISH studies identify the i(20q-) anomaly as a der(20)del(20)(q11q13)idic(20)(p11).

Fluorescence in situ hybridization (FISH) analyses were performed on six of seven patients who had been reported in 2004 to have an i(20q−) anomaly expressed as ider(20)(q10)del(20)(q11q13). The i(20q−) was investigated with a series of probes: a centromere‐specific probe for chromosome 20, two paint probes for 20p and 20q, and a panel of locus‐specific probes prepared from BAC/PAC clones mapped to 20p. The results showed that: (1) i(20q−) was a dicentric chromosome; (2) both of its arms comprised a deleted 20q and a small part of 20p near the centromere of chromosome 20; and (3) the breakpoints and reunion sites of i(20q−) differed, residing in the region 20p11.21–20p11.22 delineated by BAC/PAC clones RP11‐96L6 and RP13‐401N8. Thus, i(20q−) could be more precisely described as a der(20)del(20)(q11q13)idic(20)(p11).

Isolated Tetrasomy 8 in Minimally Differentiated Acute Myeloid Leukemia (AML-M0)

Tetrasomy 8 as a sole anomaly in hematological disorders is relatively rare. To the best of our knowledge, only 19 such cases have been described in the literature to date. Of them, acute myeloid leukemia (AML) in 13 (M1, one; M2, three; M4, one; M5, eight), acute lymphoblastic leukemia(ALL) in one, myelodysplastic syndrome(MDS) in 3, polycythemia vera(PV) and myelofibrosis(MF), one case each. Their median survival was 20 weeks. Here, we report the first case of a 29-year-old man with minimally differentiated AML (AML-M0) displaying a tetrasomy 8 clone. Immunophenotyping showed positivity with CD33, CD34 and intracellular MPO, but all lymphoid markers tested were negative. Conventional cytogenetics of bone marrow cells showed 84.9% of metaphases with tetrasomy 8 in addition to 15.1% with normal diploidy. However, Fluorescence in situ hybridization(FISH) using a centromeric probe specific for chromosome 8 revealed trisomy 8 in 14.2% of interphase nuclei besides tetrasomy 8 in 82.4%. The patient died four weeks after diagnosis without therapy. In conclusion, these findings suggest that tetrasomy 8 is associated with a heterogeneous group of myeloid disorders and heralds a bad prognosis. It may be a consequence of clonal evolution of trisomy 8.