Translocations (5;17) and (7;17) in patients with de novo or therapy-related myelodysplastic syndromes or acute nonlymphocytic leukemia. A possible association with acquired pseudo-Pelger-Hu?t anomaly and small vacuolated granulocytes

Twelve patients [two with de novo myelodysplastic syndrome (MDS), four with secondary MDS, five with de novo acute nonlymphocytic leukemia (ANLL), one with secondary ANLL] showed a 17p deletion resulting from translocations involving 17p: t(5;17)(p11;p11) in four cases, t(7;17)(p11;p11) in six cases, complex (5;17)(q23;p12) translocation with dicentric chromosome in one case, and t(17;?)(p11-12;?) in the remaining patient. All these structural anomalies were observed in hypodiploid clones associated with total or partial monosomy of chromosomes 5 and 7 (12 cases), monosomy 12 (five cases), monosomy 3 (four cases), and monosomy 4 (three cases). Median survival was only 3.3 months (range 3 days to 8 months). Striking features were observed in bone marrow mature granulocytes: all but one case had a pseudo-Pelger-Hu?t anomaly in a significant number of granulocytes, and eight patients had granulocytes with reduced size and clear cytoplasmic vacuoles. Careful cytological review of 51 patients with MDS or ANLL and various cytogenetic anomalies was performed for comparison: vacuolated granulocytes were a very uncommon finding. On the other hand, eight patients had a pseudo-Pelger-Hu?t anomaly, which correlated significantly with total monosomy 17 in these patients. A possible correlation between cytological anomalies and cytogenetic data is discussed, and the role of 17p in the nuclear segmentation of granulocytes is stressed.     

Cytogenetic and FISH studies of abnormal X chromosomes in a patient with ANLL.

We report a case of idic(X)(q13),r(X)(p22q13), and del(X)(:p11-->cen-->q11:) in a 71-year-old female patient with de novo acute nonlymphocytic leukemia (ANLL), FAB-M4. The abnormal X chromosomes of this patient were identified cytogenetically by G-banding technique and were further confirmed by fluorescence in situ hybridization (FISH) using an alpha-satellite probe to chromosome X centromere. The features of this are compared with other cases reported in the literature.     

Translocation (8;21) and its variants in acute nonlymphocytic leukemia. The relative importance of chromosomes 8 and 21 to the genesis of the disease

Chromosome analysis was performed in 25 patients with acute nonlymphocytic leukemia (ANLL), mostly of the M2 type. Eighteen had the standard translocation, t(8;21)(q22;q22), four had complex translocations involving 1p36, 11p13, 17p11, and 17p23, respectively, with chromosomes 8 and 21, and the remaining three patients had simple translocations, one with t(3;21)(p14;q22) and two with t(16;21)(p11;q22), without involving chromosome 8. Chromosome abnormalities additional to t(8;21) and its variants that were most frequently observed were -X, -Y, and del(9). Complex translocations are thought to be derived from the standard translocation and to be essentially similar in nature. The finding that chromosome 21 was involved in all of the standard, simple, and complex translocations, and that chromosome 8 was not involved in simple variants suggest a greater weight of chromosome 21 in the relative importance of the two chromosomes to the genesis of ANLL.     

Translocations and deletions with breakpoint on 21q are nonrandomly associated with treatment-related acute nonlymphocytic leukemia and preleukemia

Six of 70 (8.6%) consecutive cases with therapy-related acute nonlymphocytic leukemia (ANLL) or preleukemia had a translocation or deletion with a breakpoint on 21q. Such aberrations were seen in only one of 200 (0.5%) consecutive cases of de novo ANLL examined at our laboratory. The figures reflect a 17.1-fold increased incidence of 21q aberrations in therapy-related ANLL or preleukemia, compared with ANLL de novo. The difference is highly significant (p = 0.003). The increased incidence of 21q aberrations in therapy-related myelodysplastic syndromes was confirmed by literature studies. Band 21q22 was most often involved. Cases with t(8;21), which is strongly associated with the M2 variant of ANLL, or cases with i(21q), which is supposedly due to a centromeric misdivision, were not included in the count. It is concluded that the 21q aberrations are associated with treatment-related ANLL or preleukemia with at least the same degree of specificity as aberrations of #5 and #7.     

Chromosome studies on 30 Chinese patients with acute nonlymphocytic leukemia in Taiwan

Cytogenetic studies were performed on 32 consecutive Chinese patients with de novo acute nonlymphocytic leukemia (ANLL) in Taiwan. Of the 30 patients with adequate specimens, 20(66%) had clonal chromosome abnormalities. Structural rearrangements were detected in 18 of them. Seven (four were children) of the 16 patients with M2 ANLL had t(8;21). All six patients with acute promyelocytic leukemia (APL; M3 subtype) had t(15;17). Two patients with M4 type leukemia and abnormal bone marrow eosinophils had inv(16)(p13q22). Another M4 patient with a mild increase of morphologically normal eosinophils in the bone marrow had an abnormal chromosome #16, t(1;16)(q21;p13) in which 16q22 was not involved. One patient with M5 ANLL had t(9;11). Only two patients had a numerical change as the sole abnormality. None of the patients had loss or deletion of chromosome #5 or loss of chromosome #7, and only one had a deletion of 7q. This study revealed a high incidence of t(8;21), t(15;17), and a low incidence of -5/5q- or -7/7q- in Chinese patients with ANLL.     

Characterization of two marker chromosomes in a patient with acute nonlymphocytic leukemia by two-color fluorescence in situ hybridization

A patient with acute nonlymphocytic leukemia (ANLL), M5b according to French-American-British (FAB) classification, showed monosomy 16, an extra 1p−, and a 21q+. These derivative chromosomes could not be defined by GTG-banding. For better characterization, we performed two-color fluorescence in situ hybridization (FISH) experiments applying DNA libraries from sorted human chromosomes, chromosome-specific repetitive probes, and a band-specific YAC-clone. With these FISH studies the karyotype could be characterized as 46,XY,+der(1)t(1;21)(p11;?),−16,der(21)t(16;21)(p11.1;q22).     

Cytogenetics of three cases of ANLL M2 and M4. Involvement of chromosomal region 8q22 in all three but 21q22 in only one

Cytogenetic investigation of the bone marrow of two patients with acute nonlymphocytic leukemia (ANLL), French-American-British Cooperative group (FAB) classification M2, revealed a translocation (8;22)(q22.1;q13.3), without involving chromosome 21, and a variant translocation (8;21)(q22;q22). These findings, together with a del(8)(q22) found in a patient with refractory anemia, erythroblastic (RAEB)-t with progression to acute myelogenous leukemia (AML)-M4, are discussed in relation to the possible role of abnormalities of chromosomes 8 and 21 in the oncogenesis of ANLL M2 and M4.     

Secondary chromosome aberrations in the acute leukemias

Information was retrieved from a computer-based data bank about additional chromosome aberrations in patients with acute lymphatic or nonlymphatic leukemia (ALL or ANLL) and one of the following primary rearrangements: In ALL t(9;22), t(11;14), t(1;19), t(4;11), t(8;14), and del(6q); in ANLL t(9;22), t(6;9), t(8;21), t(15;17), t(9;11), inv(16), and del(20q). The distribution of secondary changes was nonrandom. Chromosomes #1, #7, #8, and #9 were frequently involved in both disease groups, albeit with some pointed differences regarding the types of rearrangements making up the majority of aberrations. Chromosome #6 was clearly more affected in ALL, whereas, loss of a sex chromosome was largely restricted to ANLL patients. Differences between specific subtypes were detectable in both ALL and ANLL. Sex chromosome loss occurred almost exclusively in patients with t(8;21), who also tended to have del(9q) and/or trisomy 8. On the other hand, patients with t(15;17) often had del(7q) or monosomy 7, trisomy 8, and del (9q) as part of their karyotypes. None of the patients with inv(16) had del(9q). Instead, structural aberrations of chromosomes #7, #16, and #19 were fairly numerous in this subgroup, as was trisomy 8. Structural changes of #1, particularly translocations and duplications, were especially frequent in ALL patients with primary rearrangements t(8;14) or del(6q). In both ALL and ANLL, patients with t(9;22) had similar additional changes, often +8, -7, and/or +Ph. The findings indicate that the initial cytogenetic change is an important factor in determining the nature of subsequent chromosomal abnormalities developing in the malignant clone.     

Complex chromosomal abnormalities in acute nonlymphocytic leukemia

A comparison of chromosome abnormalities between 31 cases of de novo acute nonlymphocytic leukemia (ANLL) with complex karyotypes and 30 cases of secondary ANLL or dysmyelopoietic syndromes (DMS) revealed significant differences. Hyperdiploidy and partial or complete monosomy 5 were more frequent in complex de novo ANLL, whereas, hypo or pseudodiploidy and partial or complete monosomy of chromosome #7 were more frequent in secondary ANLL/DMS. Monosomy 17 and partial deletion of the short arm of chromosome #12 (12p-) occurred more commonly in de novo ANLL and secondary ANLL/DMS, respectively, but were not statistically significant. Therefore, although the abnormalities found in the two groups were of the same basic type, the frequencies of occurrence differed. These findings suggest the role of as yet unknown agents in the etiology of some so called de novo ANLL, and that different mutagenic or carcinogenic agents may produce different chromosomal abnormalities.     

Cytogenetic analysis in children with acute nonlymphocytic leukemia.

In this work we present the results of cytogenetic analysis of the malignant cells in 27 children with acute nonlymphocytic leukemia (ANLL). The aim of our investigations was to determine the frequency and types of chromosome aberrations in our population of children with ANLL. Successful cytogenetic analysis was carried out in 24 (89%) patients. Aberrant karyotypes of malignant cells were established in 58% of the cases. The most frequent chromosomal abnormality was t(8;21), identified in 5 (20.8%) patients, i.e., 4 of 10 M2-ANLL. Aberration frequency of chromosome 11 was 16.6% and was identified in 3 of 8 M5-ANLL. Trisomy 8 and monosomy 7 were identified in one patient each with M3 and M2-ANLL, respectively. del(13), a rare chromosome aberration in hemoblastoses, was found in a child with M1,t(8;21) and the loss of chromosome Y. Translocation t(1;11;21) with a break in regions 1q23, 11q23, and 21q22, is unusual and was identified in a boy with M2-ANLL; it can be considered as a variant form of the t(8;21).     

Complex Ph translocations in chronic myeloid leukemia

Monosomy for chromosome 5 or a portion of the long arm is a common finding in acute nonlymphocytic leukemia (ANLL) and myelodysplastic syndrome (MDS), especially when the disorder is therapy related [1,2]. If only a portion of chromosome 5 is missing, the loss is usually accomplished by interstitial deletion of various bands, most frequently q12-14 to q31-33 [3]. Occasionally monosomy for 5q is the result of a translocation between chromosome 5 and another chromosome, with the loss of the derivative chromosome that contains 5q. A previously described unbalanced translocation involves chromosome 7: [der(5)t(5;7)(q11.2;p11.2)] and appears to be a recurring abnormality in these disorders [4]. We report here one case of therapy related MDS, one case of MDS which may be therapy related, and two cases of MDS with another "variant" 5q - abnormality, namely a derivative chromosome 3 composed of most of the short arm of chromosome 5 and the long arm of chromosome 3: [der(3)t(3;5)(?p11;?p11)].     

Cytogenetic,clinical, and cytologic characteristics of radiotherapy-related leukemias

From 1978 to 1985, we observed eitht cases of acute nonlymphocytic leukemia or preleukemia, three cases of acute lymphoblastic leukemia, and three cases of chronic myeloid leukemia in patients previously treated exclusively with radiotherapy for other tumor types. The latent period from administration of radiotherapy to development of leukemia varied between 12 and 243 months. Clonal chromosome aberrations reported previously as characteristic of acute nonlymphocytic leukemia following therapy with alkylating agents were observed in three of the eight patients with acute nonlymphocytic leukemia (5q− and −7) and in two of the three patients with acute lymphoblastic leukemia (−7 and 12p−). All three patients with radiotherapy-related chronic myeloid leukemia presented a t(9;22)(q34;q11). The results suggest that cytogenetic characteristics may reflect the etiology in radiation-induced acute leukemias, whereas radiation-related chronic myeloid leukemia does not seem to differ chromosomally from de novo cases of the disease.     

1058例急性非淋巴细胞白血病的细胞遗传学分析

目的：评估我国大系列急性非淋巴细胞白血病（acute nonlymphocytic leukemia,ANLL)的核型状况。方法：采用直接法和短期培养法制备骨髓细胞染色体,并以R显带为主、G显带为辅对1058例初治的ANLL患者进行染色体核型分析。结果：本组中630例（60％）有克隆性染色体异常。主要异常核型共有25种,其中11种为特异性染色体重排,见于481例,占核型异常患者总数的76％。单纯＋8（21例）为常见的数目异常。t(15;17)(211例）和t（8;21）（200例）为最常见的结构异常。1．1％的M2、72％的M3、71％的M4EO、50％的M2、6％的M5和1．4％的M2分别有t（7;11）、t(15;17)、inv(16)、t(8;21)、t/del(11q23)和t/del(12p)异常,而100％的t(7;11)、100%的t（15;17）、100％的inv(16)、88．5％的t(8;21）、83％的t/del(11q23)和62％的t/del（12p)分别见于M2、M3、M4E0、M2、M5和M2亚型患者。结论：联合应用R带和G带两种常规显带技术,60％的ANLL患者可检出克隆性染色体异常且主要为特异性染色体重排。它们和特定的FAB亚型相关,因而核型是ANLL诊断和分型的一项重要指标。     

Geographic heterogeneity of neoplasia-associated chromosome aberrations

Using a database comprising 13,266 cytogenetically abnormal neoplasms, the geographic heterogeneity of neoplasia-associated chromosomal abnormalities was investigated by comparing the frequencies of characteristic aberrations in consecutive series of patients with the same diagnosis. Significant frequency differences between geographic areas were found for the aberrations +8, i(17q), +19, and an additional Ph1 chromosome in chronic myeloid leukemia (CML); -5, 5q-, and +8 in acute nonlymphocytic leukemia (ANLL); t(8;21) in ANLL-M2; t(15;17) in ANLL-M3; 5q- and -7 in myelodysplastic syndromes (MDS); t(9;22) and +21 in acute lymphocytic leukemia (ALL); t(14;18) in follicular lymphoma; -8 and -22/22q- in meningioma; and structural abnormalities of 12q in pleomorphic adenoma of the salivary glands (PAS). No geographic incidence variation was detected for -7 and +21 in ANLL; +8 in MDS; 6q- and +8 in ALL; +12 in chronic lymphocytic leukemia; 6q- in non-Hodgkin's lymphoma (NHL); t(8;14) in Burkitt's lymphoma; t(11;22) in Ewing's sarcoma; i(12p) in germ cell tumors; 1p- in neuroblastoma; structural abnormalities of 3q, 8q, and 9p in PAS; or 3p- in renal cell carcinoma. Intraregional frequency similarities between cytogenetically identical abnormalities in related tumor types were also analyzed. No significant correlations were found regarding the incidence of 5q- in ANLL and MDS, 6q- in ALL and NHL, -7 in ANLL and MDS, +8 in ANLL and CML, +8 in ANLL and MDS, +8 in ALL and ANLL, or +21 in ALL and ANLL. The findings indicate that some geographic heterogeneity of tumor-associated aberrations exists both in hematologic neoplasms and in solid tumors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Three new cases of chromosome 3 rearrangement in bands q21 and q26 with abnormal thrombopoiesis bring further evidence to the existence of a 3q21q26 syndrome.

Defects of 3q in bands q21 and q26 have been reported in more than 70 cases of acute nonlymphocytic leukemia (ANLL), myelodysplastic syndrome (MDS), and myeloproliferative disorder (MPD) in blast crisis. In this paper three additional patients are described: patient 1 with refractory anemia with excess of blasts in transformation (RAEB-T) and inv(3)(q21q26), patient 2 with RAEB-T and t(3;3)(q21;q26), and patient 3 with myelofibrosis with myeloid metaplasia (MMM) in blast crisis and inv(3)(q21q26). In addition to 3q rearrangements, monosomy 7 and del(7)(q22q36) were observed in patients 1 and 2, respectively. In the three patients, the most characteristic clinical features were elevated platelet counts, marked hyperplasia with dysplasia of the megakaryocytes, and poor prognosis. Although disturbance of thrombopoiesis was not systematically observed in all patients with t(3;3)(q21;q26), inv(3)(q21q26), and ins or dup(3)(q21----q26), study of the 77 cases reported and of the three cases presented here brings further evidence to the existence of a cytogenetic syndrome involving bands q21 and q26 simultaneously, which represents a subtype of ANLL, MDS, and MPD, characterized by normal or elevated platelet counts, hyperplasia with dysplasia of megakaryocytes, multilineage involvement, young median age of patients with MDS, preferential involvement of women in t(3;3), high incidence of chromosome 7 defects in MDS and ANLL, short duration of the MDS phase, no response to chemotherapy, short survival, and por prognosis.     

Cytogenetics of childhood acute nonlymphocytic leukemia

Interest in more precise subclassification of the acute leukemias by cytogenetic criteria led us to identify and characterize the full range of chromosomal abnormalities in 121 children with de novo acute nonlymphocytic leukemia (ANLL). Only 21% of the cases had normal karyotypes; 62% had consistent or recurrent alterations, most commonly inv(16) or del(16), t(8;21), t(15;17), t(9;11), t(11;V) or del(11), and -7 or 7q-; and 17% had miscellaneous, apparently random, clonal abnormalities. Statistically significant associations between chromosomal abnormalities and the morphologic/cytochemical subtypes of ANLL, defined by criteria of the French-American-British (FAB) cooperative group were demonstrated for the t(8;21) in M1 and M2 leukemia, t(15;17) in M3, t(9;11) in M5, and translocations involving 11q23 other than t(9;11) [t(11;V)] or del(11q) in M4 and M5. The chromosome 16 inversion was not restricted to the M4 subtype, as is generally reported, and was not uniformly associated with increased and/or abnormal marrow eosinophils. None of these 121 cases were characterized by the Philadelphia chromosome, nor did any have the t(6;9), t(16;16), or inv(3), which have been noted previously in this disease. In addition to confirming several recognized correlations between recurrent structural chromosome abnormalities and FAB subtypes, this study identified novel abnormalities that have not been reported by others. It also disclosed an unusual heterogeneity of chromosome 16 abnormalities with respect to their distribution among FAB subtypes, their association with marrow eosinophilia, and their participation with other chromosomes in translocations.     

Translocation 2;11 and other significant chromosome changes in acute monoblastic leukemia (M5) with clonal evolution: sequential clinical and cytogenetic studies

An elderly woman presented with pancytopenia resulting from acute monoblastic leukemia (AMoL) type M5a. At the time of diagnosis, the marrow metaphase studies revealed a pseudodiploid idiogram: 46,XX,t(2;11)(q37;q23),(t(7;9;10)(q22;q22;p13). At relapse, 7 months later, a clonal derivative of the initial pseudodiploid pattern was identified. Though alterations of chromosome regions 7q22 and 9q22 are frequently seen in acute nonlymphocytic leukemia (ANLL), 11q structural anomalies are even more specific for this group of leukemias, and the involvement of band 11q23 is particularly striking in AMoL. Various chromosomes may take part in translocations with chromosome #11, but the participation of chromosome #2 as in this case is apparently rare.     

Chromosomal abnormalities in childhood acute nonlymphocytic leukemia (M4).

A new reciprocal, apparently balanced translocation between chromosomes 7 and 22, i.e., t(7;22)(p22;q13), in association with inv(16)(p13q22) in a child with acute nonlymphocytic leukemia (M4) is reported. Five percent of her bone marrow cells contained both of these aberrations while 90% of her cells have the pericentric inversion of chromosome 16 as the sole abnormality. A clonal evolution of the unusual cell line may be associated with atypical clinical presentation. The presence of inversion 16 in adults has a better prognosis as compared with children. A concise review on the cytogenetic findings in children with ANLL(M4) is also provided.     

Cytogenetics of agnogenic myeloid metaplasia: a study of 61 patients

Agnogenic myeloid metaplasia (AMM) or idiopathic myelofibrosis is a chronic myeloproliferative disorder characterized by fibrotic bone marrow, extramedullar haematopoiesis, and a leukoerythroblastic picture in circulating blood. The cytogenetic data on AMM are scanty and no recurring chromosome abnormality has been associated with the natural course of this disease. Trisomy 1q, del(13q), del(20q), and trisomy 8, appear in about two thirds of patients with demonstrable chromosome aberrations. We report on the cytogenetic analyses of 61 consecutive patients with AMM studied at diagnosis. The metaphases could not be found in 10/61 (16.4%) patients, and chromosome studies were successful in 51 patients. Twenty-one patients (41%) had an abnormal clone, whereas 30 (59%) patients had a normal karyotype. Most frequent pathological findings included trisomy 8 (either alone or within a complex karyotype) in five patients, aberrations of chromosome 12 (translocation in two, monosomy in two, and trisomy in one patient), and aberrations of chromosome 20 (interstitial deletion in two, monosomy in two, and trisomy in one patient). We also detected aberrations of chromosome 13 (translocation in two and an interstitial deletion and trisomy in one patient each) and chromosome 18 (derivative 18 in two patients and a monosomy and deletion in one patient each). Three patients exhibited complex aberrations involving several chromosomes, sometimes with a mosaicisam. A near-tetraploid karyotype was observed in a single patient. Balanced translocations [t(2;16)(q31;q24), t(5;13)(q13;q32), t(12;13)(p12;q13), and t(12;16)(q24;q24)] were present in four patients. While the series of patients studied displayed chromosomal aberrations that are frequently observed in AMM, we found some new abnormalities (balanced translocations and polyploidy) that are rarely observed in AMM.     

A myelodysplastic syndrome with marrow eosinophilia terminating in acute nonlymphocytic leukemia, associated with an abnormal chromosome 16

A patient presented with a myelodysplastic syndrome and bone marrow eosinophilia that evolved six months later into an acute nonlymphocytic leukemia (ANLL). Cytogenetic analyses of the bone marrow revealed 86% of the metaphases with 45,X-Y,inv(16)(p13;q22),t(11;17) (q11;q25),del(21)(q13) and 14% of the metaphases with the same abnormalities but with a Y chromosome. The association of ANLL, bone marrow eosinophilia, and abnormal chromosome 16 has previously been reported and has been suggested to have a favorable prognosis. Our patient is unique in that ANLL was preceded by a preleukemic phase associated with bone marrow eosinophilia. When complete remission was achieved, the bone marrow cytogenetics returned to normal, and the eosinophilia disappeared.