FIG 1 - uploaded by Uzi Gafter
Content may be subject to copyright.
Lymphoblasts in bone marrow aspiration biopsy. Wright's stain, x 1,200. 0002-9173/79/1200/1018 $00.85 © American Society of Clinical Pathologists
Source publication
Examination of the bone marrow of a 63-year-old man who had acute lymphoblastic leukemia revealed a population of cells with 32 chromosomes and another population with 64 chromosomes, the karyotypical exact duplicate of the first clone. The karyotypic evolution was studied and the findings compared with those described in two similar cases previous...
Similar publications
The occurrence of additional cytogenetic abnormalities (ACA) is common in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) but is of unknown significance in the tyrosine-kinase inhibitor (TKI) era. We retrospectively analyzed data from a consecutive case series of adults with Ph+ ALL who had undergone allogeneic hematopoietic...
A case of severe thrombocytopenia with multiple bony lytic lesions is presented. Bone marrow examination revealed caseating granuloma suggestive of disseminated tuberculosis. There was no evidence of pulmonary involvement with tuberculosis and the patient didn't have any other comorbid condition. The patient responded well to standard antituberculo...
Citations
... Первое описание острого лимфобластного лейкоза с гипоплоидным кариотипом с 32 хромосомами и удвоенного субклона с 64 хромосомами появилось в 1979 г. [17]. Неблагоприятное прогностическое значение гиподиплоидного кариотипа было определено еще в 80-х годах ХХ века [18][19][20]. ...
The detection of genetic markers associated with poor prognosis is crucial to the selection of an appropriate treatment plan for B-cell precursor acute lymphoblastic leukemia (BCP-ALL). A hypodiploid karyotype in patients with BCP-ALL has an unfavorable impact and serves as a criterion for the stratification of patients into a high-risk group. However, the survival rates of patients with a hypodiploid karyotype remain poor. Russian treatment protocols for childhood acute lymphoblastic leukemia do not include a hypodiploid karyotype in risk stratification criteria. In order to determine the prognostic value of a hypodiploid karyotype and the clinical characteristics of BCP-ALL in patients with a hypodiploid karyotype, we analyzed the survival rates of 2,700 patients included in a multicenter study. Our study was approved by the Independent Ethics Committee and the Scientific Council of the D. Rogachev NMRCPHOI of the Ministry of Healthcare of the Russian Federation. All patients underwent karyotyping and fluorescence in situhybridization (FISH) testing. A hypodiploid karyotype was detected in 27 patients. Eighteen out of 27 patients had a hypoploid clone (according to karyotyping results), 2 patients had a doubled near-haploid clone (according to karyotyping and FISH results); in 7 patients with a normal karyotype or in the absence of mitosis, hypodiploidy was determined only by FISH test. BCP-ALL with hypodiploidy is usually associated with increased WBC count at disease onset. The median WBC count in the study group was 24.2 (3.4–206.0) × 10 ⁹ /l vs 10.3 (0.2–1290.0) × 10 ⁹ /l in the control group. The number of patients with initial leukocytosis < 30 × 109/l in the study group was significantly lower than in the control group (p< 0.062). Remission was achieved in 26/27 patients. The event-free survival rates in patients with hypodiploidy were significantly lower than in those without hypodiploidy: 50 ± 11% vs 72 ± 8% (p< 0.0001). The overall survival was 64 ± 10% and 90 ± 1%, respectively (p< 0.0001). The cumulative incidence of relapse in patients with a hypodiploid karyotype was higher (42.6 ± 10.9%) than in the controls (22.3 ± 8.1%) (p< 0.0001). The patients who received more intense treatment for intermediate- and high-risk groups showed better survival rates than those in the standard-risk group: 62 ± 13% vs 40 ± 15% (р= 0.59); the cumulative incidence of relapse according to the risk group was 26.4 ± 12.1% and 60 ± 16.9%, respectively (р= 0.19).The highest risk of relapse was observed in a group that included patients with near-haploidy and low hypodiploidy (26–39 chromosomes; 52.9 ± 14.4%). The event-free survival in this group was 36 ± 13%. The results of treatment of patients with BCP-ALL and hypodiploidy according to the national guidelines turned out to be comparable to the international ones. Patients with BCP-ALL and hypodiploidy should be initially stratified to the most intense treatment arm. In order to identify patients with hypoploidy, standard karyotyping is required; where needed, it can be supplemented by FISH analysis
... In the large majority of cases the 24-36-chromosome clones coexist with others that show duplicated chromosome numbers (Table I). In cases where such cells have been karyotyped, they represent exactly or almost exactly duplicated chromosome complements (3,7,9,10,12,14,17). Evidence from the occurrence of marker chromosomes in cells with single and double complements indicate that the double complement cells have arisen from those with a single complement rather than vice versa (12,14). ...
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.
Our knowledge of chromosome patterns in human leukemia has progressed remarkably since the advent of banding techniques, which permit the precise identification of each human chromosome and of parts of chromosomes as well. First, the nature of the Ph1 chromosome in chronic myelogenous leukemia (CML) and the occurrence of nonrandom abnormalities in addition to the Ph1 chromosome in the blastic phase of CML were established. Second, specific chromosome abnormalities in acute nonlymphocytic leukemia (ANLL) were identified; these changes were found to be closely related to certain clinical features and also to the morphology of the leukemic cells. More recently, nonrandom abnormalities in acute lymphoblastic leukemia (ALL) have been established, and their correlation with the clinical features of the disease has been clarified. We will review chromosome abnormalities that occur in leukemia, with emphasis on their clinical significance, and then we will delineate the similarities and the differences in the chromosome patterns observed in adult and childhood leukemia.
Blast cells from a 39-year-old man in the blastic phase of chronic myeloid leukemia, with a benign phase of 15 years duration, as well as a cell line arising from this cell population, were studied. Cellular morphology, cytochemical staining pattern, and absence of terminal deoxynucleotidyl transferase showed the blast cells to be of myeloid character. Cytogenetic studies revealed the presence of two near-haploid cell populations with +8 and +8,+15, respectively, both of them containing the translocation t(9;22) in the original tumor cell sample. The cell line derived from this patient's leukemic cell sample contained both near-haploid and hyperdiploid clones, the hyperdiploid clones being multiples of the near-haploid clone(s). All of the clones carried the t(9;22) in the form of a Philadelphia chromosome.
In der vorliegenden Arbeit wurde untersucht, inwieweit die CGH zur Charakterisierung komplexer Tumorkaryotypen bei hämatologischen Neoplasien mit mehr als 50 Chromosomen beitragen kann. Erstmals wurden in dieser Arbeit CGH-Untersuchungen bei der ALL des Erwachsenen durchgeführt und aus archivierten Zellsuspensionen von Leukämien DNA für die CGH gewonnen. Es wurden 20 Fälle hämatologischer Neoplasien mit Chromosomensätzen aus über 50 Elementen bei Erwachsenen mittels CGH untersucht. Dabei handelte es sich in 16 Fällen um eine ALL und in je zwei Fällen um eine AML oder ein NHL. Bei acht der 20 Patienten wurde die DOP-PCR nach Chelexaufbereitung eingesetzt, um aus archivierten Zellsuspensionen DNA für die CGH zu gewinnen. Durch die vorliegende Untersuchung konnte gezeigt werden, dass es auch bei Leukämien möglich ist, aus archiviertem Zellmaterial CGH-Untersuchungen durchzuführen. Es wurde deutlich, dass sowohl die Referenz- als auch die Test-DNA mittels DOP-PCR aufbereitet werden muss, um falsch positive Ergebnisse zu verhindern, und dass es sich bei diesen falsch positiven Befunden um wiederkehrende Ereignisse handelt, die für eine spezifische, durch die DOP-PCR verursachte Fehlerquelle sprechen. Die ALL>50 des Erwachsenen besitzt im Gegensatz zur ALL>50 des Kindesalters keine ausgezeichnete Prognose. Die vorliegende CGH-Untersuchung ließ nicht erkennen, dass unterschiedliche Verteilungsmuster hinzugewonnener Chromosomen diese Unterschiede bezüglich der Heilungsrate erklären. Bei den vorliegenden Fällen mit hyperdiploider ALL waren die Chromosomen 4, 6, 10, 14, 17, 18, 21 und X mit etwa den gleichen Häufigkeitsmustern wie bei Kindern hinzugewonnen. Die CGH konnte wesentlich zur Klärung der chromosomalen Zusammensetzung beitragen und korrigierte die Zytogenetik bezüglich der Häufigkeitsverteilung hinzugewonnener, prognostisch relevanter Chromosomen. Partielle Imbalancen in der CGH lassen Rückschlüsse auf unbalanciert vorliegende strukturelle Aberrationen zu. Bei der ALL>50 des Erwachsenen fand sich in der kombinierten Auswertung von zytogenetischem Befund und CGH ein im Vergleich zu Kindern erhöhter Anteil an strukturellen Veränderungen, was eine Ursache für die schlechtere Prognose der ALL>50 bei Erwachsenen sein könnte. Die CGH konnte bei der ALL>50 partielle Imbalancen aufdecken, die zytogenetisch nicht gesehen wurden und die von prognostischer Bedeutung sind: Die CGH konnte 9p-Verluste detektieren, von denen bekannt ist, dass sie auf eine schlechtere Prognose hindeuten und dass sie zytogenetisch häufig nicht erkannt werden. In den Regionen 2q21q31, 3q24q26 und 13q21q32 fanden sich partielle Zugewinne, bei denen es sich möglicherweise um spezifische, wiederkehrende Aberrationen der ALL>50 des Erwachsenen handelt. Die CGH konnte zur Aufklärung der Entstehungsmechanismen chromosomaler Zugewinne bei der ALL beitragen: Bei einem Fall mit einem nahezu triploiden Chromosomensatz erhärtete die CGH die Vermutung, dass dieser durch Verdopplung aus einem hypodiploiden Chromosomensatz hervorgegangen ist. Bei einem tetraploiden Fall detektierte die CGH partielle Imbalancen entsprechend einem Isochromosom 17q, das zytogenetisch nicht erkennbar war. Dies deutet auf die Entstehung des tetraploiden Karyotyps durch Verlust des Tumorsuppressorgens TP53 und nachfolgender Verdopplung des Karyotyps hin. Bei den zwei untersuchten Fällen mit leukämischen Non-Hodgkin-Lymphomen konnte die CGH Imbalancen detektieren, die zytogenetisch nicht erkennbar waren und die mit aggressiven Verlaufsformen, leukämischem Verlauf oder der Ausbildung tetraploider Karyotypen assoziiert sind: Verluste im Bereich 17p, Zugewinne im Bereich 1q, 3q, 8q, 13q und 18q. In der Region Xq28 fand sich ein weiterer Hinweis für ein in dieser Region vermutetes Onkogen für Non-Hodgkin-Lymphome. Bei einem tetraploiden Fall von AML konnte die CGH Befunde liefern, die nahe legen, dass es sich bei einem Isochromosom 8q um einen Marker für eine sekundäre myeloische Leukämie handelt, und es im Rahmen einer sekundären Leukämie zu einer Polyploidisierung des Chromosomensatzes kam. Einschränkend fand sich erneut die limitierte Aussagekraft der CGH bei einem geringen Anteil von Leukämiezellen in der Probe und ganzzahligen Vermehrungen des Chromosomensatzes. Im Rahmen der vergleichenden Auswertung von zytogenetischen und CGH-Befunden wurde zusätzlich deutlich, dass eine kritische Auswertung der CGH die zytogenetischen Befunde und den Ratioprofilverlauf der CGH heranziehen sollte, um die Gefahr falsch positiver Befunde so gering wie möglich zu halten. We used comparative genomic hybridization to study the chromosomal status of 20 adult patients with haematological malignancies (16 ALL, 2 AML and 2 NHL). In 8 cases CGH was performed with DNA recovered from fixed cells by the use of chelating resins and universally amplified by DOP-PCR. The results did not differ from those performed with conventionally prepared DNA if normal genomic DNA that had also undergone DOP-PCR was used as reference sample. The childhood ALL > 50 chromosomes is associated with a favorable prognosis. No such favorable prognosis can be identified in adult ALL > 50. A certain pattern of chromosome gains und losses has been described in ALL > 50. In this study the hyperdiploid cases did have the same distribution of gained chromosomes as described in childhood ALL (4, 6, 10, 14, 17, 18, 21, X). So the difference in prognosis may be not explained by a different chromosome pattern. Structural chromosomal abnormalities in general are associated with a poor treatment outcome. The combination of CGH und conventional karyotyping provides more precise information about structural chromosomal abnormalities than conventional cytogenetics alone. In the combined analysis we found that the amount of structural chromosomal abnormalities in our adult patients with ALL > 50 was higher than the amount described in children. This result may explain the difference in treatment outcome between children and adults with ALL > 50. The CGH revealed losses at 9p which were not detected by cytogenetic analysis. At 2q21q31, 3q24q26 and 13q21q32 partial gains were detected, possibly nonrandom abnormalities in adult ALL > 50. In a case with tetraploid karyotype CGH found an isochromosome 17q, that possibly indicates the formation of the tetraploid karyotype by loss of tumor suppressor gene TP53 and following duplication of the karyotype. In the two cases of NHL CGH found gains of chromosomal material on 1q, 3q, 8q, 13q and 18q and losses of 17q, imbalances that are known to be associated with tumor progression and clinical outcome. At Xq28 CGH detected a gain of chromosomal material in a region where a lymphoma-associated oncogene may exist. In one case of tetraploid AML CGH revealed an isochromosome 8q and loss of 5q, both are markers of secondary acute myeloid leukemia.
Acute lymphoblastic leukemia (ALL) of childhood is frequently characterized by a hyperdiploid karyotype. Typically, most of the affected chromosomes in the abnormal clone are present in three copies. We have studied two patients with hyperdiploid ALL whose leukemic cells were atypical in that all or most of the chromosomes were present in either two or four copies, raising a suspicion that the observed karyotype arose through duplication of chromosomes in a precursor cell with a near-haploid chromosome number. Analysis of restriction fragment length polymorphisms confirmed that both cases arose from a near-haploid cell; all informative disomic chromosomes tested had loss of heterozygosity. Furthermore, the hyperdiploid karyotypes did not arise via a perfect haploid cell with exactly 23 chromosomes, because tetrasomic chromosomes remained heterozygous. These two patients probably are classified best as near-haploid cases, which often are observed to have a co-existing hyperdiploid clone with a duplicated chromosome set. The distinction between typical hyperdiploidy and hyperdiploidy arising via a near-haploid cell may be clinically important, because the prognosis for patients with a hyperdiploid karyotype is favorable in comparison to that of patients with a near-haploid karyotype.
A number of recurring chromosomal abnormalities have been identified in childhood acute lymphoblastic leukemia. Many of these correlate closely with clinical, morphologic, and immunophenotypic features present at diagnosis and are useful in predicting outcome. Furthermore, these abnormalities point the way toward understanding the biologic basis for this disease. Challenges for the future include improvement in the quality and rapidity of cytogenetic analysis, the use of molecular probes to detect specific chromosomal abnormalities accurately and efficiently, and the incorporation of cytogenetic information into planning therapy.
We present a 4-year-old girl with acute lymphocytic leukemia (ALL) and only 25 chromosomes at cytogenetic examination of her bone marrow. Severe hypodiploidy is extremely rare in childhood leukemia and is almost exclusively associated with ALL. To our knowledge only six cases with banded metaphases have been published. The chromosome number in the present case is the lowest ever reported. Our patient as well as other reported cases have disomy for chromosome 21. The prognosis for ALL with hypodiploidy is poor with a reported mean survival of 9 months. All published patients are females.
Hyperdiploidy is common in neoplastic diseases but severe hypodiploidy or near-haploidy is extremely rare. Acute lymphocytic leukemia (ALL) and blast phase of chronic myelocytic leukemia (BC/CML) are the two most common leukemias where metaphases with as low as 23 chromosomes have been reported. Recent studies have indicated that during the course of malignant development, cells undergo numerous changes, however, it is still not known whether malignant transformation proceeds or results from the near-haploid state. Retrospectively, we have examined 100 metaphases with chromosome counts of 23 to 35 in patients with CML who have not yet progressed to the blastic phase, to see whether such metaphases share any common characteristics with published cases. The unusual behavior of chromosomes 8, 17 and the presence of Ph-chromosomes in 85% of the cells are highly unique features in our study. These observations are compatible with those found in BC/CML patients reported earlier. Therefore, it is hypothesized that selective chromosome loss is a gradual phenomenon and one of these near-haploid clones may replace a diploid clone as the dominant component of the population during blast transformation. Several hypotheses are proposed as to the origin of such clones in malignant hematopoietic stem cells.
A case of acute lymphoblastic leukemia with a severe hypodiploid chromosome constitution is reported. The modal chromosome number was 36, and the karyotype of these cells was 36,X, -X, -2, -3, -5, -7, -9, -12, -13, -15, -16, -17, -20, +21, +mar,del(1) (p13.1p22.3),inv(3)(q13.3q29). In addition to a haploid set, extra copies of chromosomes #6, #10, #14, #18, and #21 were found, as in most cases with severe hypodiploid karyotypes. A second, near-triploid cell line was also observed. An examination of chromosomal heteromorphisms suggested that the severe hypodiploid clone originated either from a near-triploid cell or from a common precursor cell.
