Cytogenetic Patterns Research Articles

Cytogenetic pattern in leukemic cells of patients with constitutional chromosome anomalies

Acquired karyotypic changes analyzed by banding techniques in 21 patients with a malignant hematologic disorder and a major constitutional chromosome anomaly, including ten patients with trisomy 21, five patients with a balanced translocation, and six patients with a sex chromosome anomaly. Detailed karyotypic findings were ascertained in 28 additional patients reported in the literature. Some striking differences were observed in the combined material of the present series and cases previously published as regards (a) distribution of morphological leukemia types among patients with different types of constitutional anomalies, and (b) incidence and type of acquired chromosomal abnormality among patients with different types of constitutional anomalies.

Non-random chromosomal aberrations associated with multiple myeloma.

Myelomatous tissue from 30 patients was assessed for cytogenetic abnormalities and one-third showed chromosomal deletions, additions, and/or rearrangements. Evidence is presented that those cases with only normal cytogenetics represent metaphase cells of nonmyelomatous tissue. The findings of our abnormal cases when added to the 18 reported in two series by others show unique cytogenetic patterns are present in this disease. From analysis of these 27 banded cases of myeloma, we conclude: (1) cytogenetic abnormalities of myeloma are not random; (2) clonal evolution may be associated with disease progression, however the abnormalities identified late in the disease are similar to those found in early myeloma; (3) cytogenetic aberrations of multiple myeloma differ considerably from those of chronic lymphocytic leukemia, non-Hodgkin's lymphoma, and acute lymphocytic and nonlymphocytic leukemia; and (4) the myeloma karyotype often exhibits one or more of the following: rearrangements involving chromosome 1 and 14, trisomy 3, 5, 7, 9 and 11, and monosomy 8 and 13. These findings have great importance for molecular biologic studies of multiple myeloma.

Associated abnormalities of chromosomes 1, 5, and 11 in dysmyelopoietic syndromes

Two patients with dysmyelopoietic syndrome presented the same cytogenetic pattern in their bone marrow cells, i.e., trisomy of chromosomes #1 and #11, and terminal deletion of chromosome #5 (q13–q14). Two similar cases have been described in the literature. It is suggested that this cytogenetic pattern could be a nonrandom event.

24-36-Chromosome clones in human malignancies. Cytogenetic interrelationships, clinical significance and patient age.

The literature has been reviewed for cases of malignant disease showing cellular clones with 24-36 chromosomes. Such cases are characterized by aggressive disease. Together the clones with 24-36 chromosomes compose a remarkably consistent non-random cytogenetic pattern, which demonstrates that different chromosomes are of different value for cellular survival and clonal propagation. Considering that the tissues of origin are very different (various solid tumours and different leukaemias), the close mutual cytogenetic relationship between the clones indicates that the cytogenetic pattern is tissue non-specific. Karyotypic non-specificity of cells with very different phenotypes is an apparent contradiction, which raises important questions concerning the relation between karyotype and phenotype.

Cytogenetic studies of bone marrow and extramedullary tissues and clinical course during metamorphosis of chronic myelocytic leukemia

Of 33 consecutive patients with chronic myelocytic leukemia, examined during metamorphosis, 82% showed chromosome abnormalities in addition to the Ph 1. Aberrations most frequently encountered were +8 (39%), +22q− (30%), and i(17q) (18%). Translocations other than the Ph 1 were observed in four cases and −Y clones in four cases. Discrepancies in the cytogenetic pattern between bone marrow and extramedullary tissues or blood were noted in a total of 15 patients. In six cases, transformation occurred in extramedullary organs at a time when it was not present in the marrow. In three cases the bone marrow transformation was preceded by a lymph node blastic infiltrate; in one case, by a skin infiltrate; and in one case, by a subdural blastoma. Clonal abnormalities additional to the Ph 1 were identified in the tumor tissue from all these cases. Patients with primary extramedullary transformation tended to have a lower median age at onset of metamorphosis, shorter survival, and higher incidence of chromosome abnormalities than the cases without extramedullary involvement. Patients with only Ph 1-positive cells and no other anomalies had a slightly longer duration of metamorphosis and longer total survival. Basophilia and thrombocytopenia were more marked in cases with i(17q) than in the rest of the series.

Chronic myelogenous leukemia and genetic events at 9q34

Assessment of cytogenetic patterns associated with chronic myelogenous leukemia (CML) suggests that genetic events at band q34 of chromosome nine are critical in the conversion of benign to malignant hematopoiesis. A break at this band is identified in almost all cases of Philadelphia chromosome (Ph1) positive CML, is also noted in some cases of Ph1 negative CML and cannot be excluded in the remaining cases. The human cellular homolog of the Abelson retrovirus oncogene (c-abl) is situated at band 9q34 and is translocated with the genetic sequences distal to the break point at this site in Ph1 positive disease. This oncogene has been shown experimentally to transform pre-B cells and it is expressed in primitive cells of the granulocytic series which are involved in CML. Although the break in CML chromosomes at 9q34 and the location of c-abl at 9q34 could be unrelated, it seems more likely that the two genetic events are associated with evolution of malignant hematopoiesis of man.

Leads from the MMWR. Cytogenetic patterns in Love Canal, NY, residents

Leads from the MMWR. Cytogenetic patterns in Love Canal, NY, residents

Chromosome banding patterns in patients with chronic myelocytic leukemia

One hundred and nine patients with Ph 1-positive chronic myelocytic leukemia were cytogenetically studied with banding methods. Seventy-eight patients were studied in the chronic phase and 39 patients in the blastic phase. The standard translocation was present in 107 cases. Two patients showed complex translocations involving chromosomes No. 6, 9, 22, 11 and No. 9, 22, 11, respectively. Ph 1-negative cells were detected in 8 cases (7%). Chromosome aberrations in addition to the Ph 1 chromosome were observed in 6 cases (8%) during the chronic phase. The karyotypic findings during the blastic phase were similar to those reported in the past [trisomy 8, iso(17q), and a second Ph 1]. The significance of Ph 1-negative cells, the geographic heterogeneity of the chromosomal aberrations, the effect of chemotherapy on the appearance of new clones, and the importance of the materials and methods used for the comparison of cytogenetic patterns at different laboratories are discussed.

Book reviewsLeukaemia. Ed. by WarnerN. L. and MetcalfD., pp. 232, 1981. A Series of Workshops on the Biology of Human Cancer. Report no. 14 (UICC Technical Report Series Vol. 61) (UICC, Geneva), Sw.fr. 44.00. $22.00. ISBN 92–9018–061–7

This essay of some 80,000 words, supported by 581 references, is to be strongly recommended as introductory reading for novices entering the field of leukaemia research. It covers broad aspects of leukaemia cell biology relating to function and cell kinetics, the differentiating features between varieties of leukaemia, including surface markers, the cytogenetic patterns encountered and the contribution of colony-forming assays.

A prognostic factor analysis for use in development of predictive models for response in adult acute leukemia.

The pretreatment characteristics of 325 adults with acute leukemia who were treated at the M. D. Anderson Hospital between 1973 and 1977 have been evaluated to assess their value as prognostic indicators. The patient population includes all patients treated with an anthracycline (Adriamycin or rubidazone), cytosine arabinoside, vincristine, and prednisone during the time period. Most patients had one of the variants of acute myelogenous leukemia (75%), and the remaining patients had acute lymphoblastic leukemia (16%) or undifferentiated leukemia (8%). Twenty-one factors were found to be significantly associated with probability of obtaining a complete response. In addition to characteristics previously known to provide prognostic information such as age, temperature status at the start of treatment, morphology, the presence of Auer rods, sex, and hemoglobin level, we identified the presence of a documented antecedent hematologic disorder and the finding of insufficient metaphases on cytogenetic analysis using the squash technique as being major prognostic variables. In addition, the pretreatment biochemical characteristics of hypoalbuminemia and elevated blood urea nitrogen and creatinine were found to adversely influence prognosis. The prognostic significance of factors such as the leukocyte count and platelet count, identified in earlier studies, was not confirmed in this group of patients. From this natural-history analysis predictive models for response have been developed using multivariate logistic regression techniques. One of these models has been used to evaluate the effect of morphology, treatment, and cytogenetic pattern on response to the combination of drugs used.

On the evolution of sex determination and the sex ratio in haplodiploid populations

Sex determination by ploidy, either of the entire genome (in haplodiploid populations) or of special chromosomes (XY or X0 systems) is a common occurrence. It is commonly held that observed sex ratios are an evolutionary consequence of the sex-determination system; for example, that the XY system helps produce and/or maintain sex ratios to 1: 1 (Edwards, 196 1; Williams, 1975). It should be noted, however, that factors such as segregation distortion in the sex chromosomes (see e.g. Curtsinger and Feldman, 1980, and references therein), sex-dependent fitness components (see e.g. Thomson and Feldman 1975, Charlesworth, 1977) as well as hermaphroditism, parthogenesis, and sex conversion (see e.g. Williams, 1975, Chapter 10) are all expected to affect the sex ratio in those XY systems for which they are relevant. On the other hand, sex ratios in species with other sex-determining systems may also be close to 1: 1 (Scudo, 1964; Spieth, 1974; Charlesworth, 1977). Thus the cytogenetic pattern can be regarded as neither a necessary nor a sufficient factor for the explanation of observed sex ratios. Nevertheless, the connection between sex determination and the sex ratio remains compelling to evolutionary theorists. The evolution of a sex ratio close to 1: 1 (or rather the evolution of sex determination which should determine such a ratio) was first explained by Fisher (1930) as a consequence of maximization of the number of grandoffspring through optimal allocation of parental investment in male and female offspring (see also Bodmer and Edwards, 1960). A crucial evolutionary assumption in Fisher’s argument is that each sex must supply

The role of chromosome 15 in murine leukemogenesis. I. Contrasting behavior of the tumor vs. normal parent-derived chromosomes No. 15 in somatic hybrids of varying tumorigenicity.

G-banding analysis was carried out on a series of hybrids derived from the fusion of a chromosome 15-trisomic murine T-cell leukemia of AKR origin and normal diploid fibroblasts or lymphocytes of the CBT6T6 strain. Due to the 14;15 translocation involved in the generation of the T6 marker, the chromosomes No. 15 and 14 derived from the normal and the tumor parent can be distinguished cytogenetically. Highly tumorigenic, in vitro maintained hybrids, and high-tumorigenic segregants of originally low-tumorigenic in vitro hybrids, selected by in vivo passage, showed a similar cytogenetic pattern. It was characterized by the amplification of the tumor-derived chromosomes No. 15 from the expected 3 to 5.5 +/- 0.2 copies and a concomitant decrease of the normal derived T(14;15)6 from 2 copies to 0.9 +/- 0.2. All other autosomes except No. 14 showed only minor random variations, around the expected number of 4 copies. The tumor-derived chromosome 14 was amplified from the expected 2 to 3 copies. The low-tumorigenic hybrids showed the opposite pattern with a decrease in the number of the tumor-derived 15 chromosome from 3 to 2.6 +/- 0.1 and the maintenance of the two normal parent derived T(14;15)6 chromosomes. These findings suggest the existence of a qualitative difference between the 15 chromosomes derived from the tumor vs. the normal parent, due to mutation or proviral DNA insertion in the tumor-derived homologue. Amplification of the change locus and a decrease in the dosage of its normal counterpart appear to favor tumorigenicity.

A four-year experience with anthracycline, cytosine arabinoside, vincristine and prednisone combination chemotherapy in 325 adults with acute leukemia.

Combination chemotherapy with an anthracycline, Adriamycin or rubidazone, cytosine arabinoside, vincristine and prednisone resulted in a complete remission rate of 62% in 325 consecutive unselected adults with acute leukemia. The results by morphologic categories were 58% for acute myelogenous leukemia (AML), 70% for acute undifferentiated leukemia (AUL), and 77% for acute lymphoblastic leukemia (ALL). The median survival was 43 weeks. Ten percent of all patients are projected to be alive and in remission at five years. The median remission duration for the whole group was 51 weeks, durations being significantly longer for AML (60 wks) than ALL (30 wks) and AUL (21 wks). Central nervous system involvement was uncommon in AML (4%), but much more common in patients with AUL (37%) and ALL (32%). One in five complete responders with AML is projected to be in their first remission at five years off all chemotherapy. Age, sex, morphology, cytogenetic pattern, temperature of presentation, and presence of a documented preceding hematologic abnormality are found to be significant variables for response and survival.

Micronuclei in erythropoietic bone marrow cells: Relation to cytogenetic pattern and prognosis in acute nonlymphocytic leukemia

The bone marrow karyotype and the frequency of micronuclei in erythropoietic bone marrow cells (Howell-Jolly bodies) were determined in 25 adults with acute nonlymophocytic leukemia (ANLL). Ten patients had exclusively normal diploid bone marrow cells; 11 had a mixture of normal and abnormal cells, and 4 had abnormal bone marrow metaphases only. The frequency of micronuclei ranged from 3 to 28/2000 erythropoietic bone marrow cells (median 10). The number of micronuclei was significantly higher in patients with abnormal metaphases than in those with normal metaphases; in patients with a mixture of normal and abnormal bone marrow metaphases there was an association between the frequency of abnormal metaphases and the number of micronuclei. A striking difference in median survival time was found between patients with low and high numbers of micronuclei, irrespective of the cytogenetic bone marrow patterns. Patients with fewer than 10 micronuclei per 2000 erythropoietic bone marrow cells had a median survival of 148 days; those with more than 10/2000 had a median survival of only 34 days (0.002 < p < 0.02).

Cytogenetics of chronic B-cell and T-cell leukemia

Chromosome data in chronic lymphocytic leukemia (CLL) are sparse. In the common form, B-cell CLL, the neoplastic cells do not usually proliferate in vitro, and apparently most reports of “normal” cytogenetic patterns reflect nonneoplastic T cells dividing in mitogen-stimulated cultures. Until better methods are developed to stimulate proliferation of CLL B cells, the nature and frequency of chromosomal abnormalities in this disorder will remain largely unknown. Chronic T-cell leukemias constitute a rare and heterogeneous group of dyscrasias, ranging clinically from typical CLL to variants of the Sezary syndrome. The neoplastic lymphoeytes respond to T-cell mitogens, and in a series of nine patients, all had cytogenetically altered clones in the peripheral blood. Banding revealed nonrandom involvement of chromosomes 2, 14, and 18, with a 14q+ marker in two cases. Sequential studies in this series have demonstrated karyotypic changes over time, correlated, in some patients, with clinical course or alterations in the lymphocytes; but the general prognostic value of such investigations remains to be determined.

Cytogenetic patterns in acute non-lymphocytic leukaemia

Chromosome banding studies of the leukaemic cells of patients with acute non-lymphocytic leukaemia (A.N.L.L.) show that both numerical and structural changes occur in 50-60% of patients examined at diagnosis. Identification of chromosomes involved in both types of change indicate that there is a non-random involvement of specific chromosomes. In addition, cytogenetic subgroups can be identified which appear to have prognostic implications. This paper reviews the results of chromosome studies in A.N.L.L. performed in the cytogenetic research unit at St St Vincent’s Hospital, from 1975 to 1978. Using short-term marrow cultures, chromosome studies were carried out on 168 patients at diagnosis; 102 were found to have abnormal karyotypes and 48 showed no chromosome abnormality. No mitoses were obtained from 18 patients. To date trypsin G-banding studies have been satisfactorily performed on 47, of whom 37 had abnormalities. The most common abnormality was trisomy 8. A specific translocation between 8 and 21 was identified in 3 patients and a 9;22 translocation in 2 others. All patients with acute erythroleukaemia, and the majority with A.N.L.L. occurring after long-term therapy for other haematological disorders, had abnormal karyotypes with multiple abnormalities. The response of these patients to therapy was poor, whereas those with specific translocations all achieved remission. Ten of 12 patients considered to have a preleukaemic syndrome showed chromosome abnormalities which were most frequently monosomy 7 or partial deletion of the long arms of chromosome 5,(5q-). Similar findings have been reported in other series, but the frequency of occurrence appears to show geographical variation. Therefore as cytogenetic patterns seem to have diagnostic, prognostic and aetiological implications in A.N.L.L., chromosome studies should always be performed at diagnosis.

Correlation between prognosis and bone marrow chromosomal patterns in children with acute nonlymphocytic leukemia: similarities and differences compared to adults

The chromosomal complement of 28 children with the diagnosis of acute nonlymphocytic leukemia (ANLL) were examined. An abnormal cytogenetic pattern was found in 50% of these patients, which is similar to the results in adults with ANLL. Unlike the reports in adult patients, however, no specific chromosomal changes were found. This observation may imply that the etiology and mechanisms by which abnormal clones develop in ANLL could differ significantly between children and adults. Those patients with chromosomal abnormalities in their initial bone marrow sample had a median survival of 7.1 mo, whereas those with a normal diploid pattern in their bone marrow had a median survival of 20.5 mo (1-sided, p = 0.04). If all metaphases were abnormal, the median survival was only 3 mo.

Correlation Between Prognosis and Bone Marrow Chromosomal Patterns in Children With Acute Nonlymphocytic Leukemia: Similarities and Differences Compared to Adults

The chromosomal complement of 28 children with the diagnosis of acute nonlymphocytic leukemia (ANLL) were examined. An abnormal cytogenetic pattern was found in 50% of these patients, which is similar to the results in adults with ANLL. Unlike the reports in adult patients, however, no specific chromosomal changes were found. This observation may imply that the etiology and mechanisms by which abnormal clones develop in ANLL could differ significantly between children and adults. Those patients with chromosomal abnormalities in their initial bone marrow sample had a median survival of 7.1 mo, whereas those with a normal diploid pattern in their bone marrow had a median survival of 20.5 mo (1-sided, p = 0.04). If all metaphases were abnormal, the median survival was only 3 mo.

Cytogenetic patterns in acute nonlymphocytic leukemia.

Analysis of chromosomal banding patterns in acute nonlymphocytic leukemia (ANLL) reveals that approximately 50% of patients have an abnormal karyotype. Although there is substantial variability, certain nonrandom abnormalities occur, e.g., +8, -7, and the 8;21 translocation (often accompanied by loss of an X or Y chromosome). The 15;17 translocation appears to be highly specific for acute promyelocytic leukemia. These abnormalities usually are not seen in remission, but reappear in relapse, sometimes exhibiting further clonal evolution; a +8 is the most frequently observed evolutionary change. Patients with ANLL following treatment of a malignant lymphoma tend to have hypodiploid modal numbers and frequently show loss of a chromosome No. 5 or No. 7.

Clonal Evolution in Atypical Chronic Granulocytic Leukemia: A Non-Philadelphia Translocation

Hemopoietic cells in chronic granulocytic leukemia (CGL) frequently contain a chromosome translocation involving chromosome 22 and another autosome, usually number 9. The translocated chromosome 22 is known as the Philadelphia (Ph) chromosome. The appearance of a second Ph chromosome is the most common cytogenetic abnormality in CGL signaling the blastic phase. For 6 yr we serially studied a man with atypical CGL whose marrow cells were marked by a translocation from chromosome 18 to chromosome 11 [46XY,t(11;18)(q23;q12)]. Three months prior to blast transformation there appeared an extra copy of the marker chromosome 18: 47XY,t(11;18)(q23;q12),+(18p11 leads to 18q12). This man presents a new cytogenetic pattern of clonal evolution in CGL. The pattern is analogous to that of the Ph chromosome and is characterized by a balanced chromosomal rearrangement and the subsequent acquisition of an extra copy of the small translocation chromosome immediately prior to blast transformation.