Complex Translocations between Chromosomes #6, #9, #22, and #11 in a Patient with Chronic Myelocytic Leukemia: 46,XX,t(6;9;22;11)(p21;q34;q11;q13)

Felix Carbonell, Elisabeth Kratt, and Karolin Neuhaus

ABSTRACT: A case of chronic myelocytic leukemia with myelofibrosis has been reported. An abnormal clane with a rearrangement of four chromosomes: 46,XX, t(6;9;22;11)[p21;q34;q11;q13] was ob- served. The possible significance of this chromosome abnormality is discussed.

INTRODUCTION

Chronic myelocytic leukemia (CML) is characterized cytogenetically by a Philadel- phia chromosome (Ph 1) in about 80% of all cases [1 - 3]. Rowley [4] has noted that the Phlusually originates owing to a translocation between chromosomes #9 and #22. Following this discovery several variant translocations of the Ph 1 have been found [5-16]. Unusual and complex Ph ~ translocations occur with a frequency varying from 2 to 10% of the cases of~CML [17-19] and their clinical significance has been recently reviewed [20]. Translocations involving more than three chromosomes are very rare and only a few cases have appeared in the literature [5,10,13,20]. The clini- cal and cytogenetic findings of a new case of CML with a complex translocation in- volving four chromosomes are described in this article.

CASE REPORT

A 64-year-old female was referred to our laboratory with a diagnosis of CML and/or myelofibrosis; a designation established on the basis of hepatosplenomegaly, throm- bocytosis, and leukocytosis. A complete blood count revealed the following: RBC, 3.4 x 106/mm3; Hb 12.2 g%, Hct 33%; WBC 192,600/mm3; platelets 578,000/mm 3. The dif- ferential count was: myeloblasts 2%; promyelocytes 8%; myelocytes 9%; metamyelo- cytes 14%; bands 12%; neutrophils 39%; eosinophils 6%; basophils 7%; monocytes 2%; and lymphocytes 1%. Leukocyte alkaline phosphatase scores were 1. The bone marrow aspirate was characteristic of CML in the chronic stage.

From the Department of Clinical Physiology and Occupational Medicine, University of Ulm, Ulm, Federal Republic of Germany.

Address requests for reprints to: Dr. Felix Carbonell, Depar tment of Clinical Physiology, University of Ulm, Oberer Eselsberg, M 24, 7900 Ulm (Danau), F.R.G.

Received December 20, 1979; accepted February 29, 1980.

©Elsevier North Holland, Inc., 1980 Cancer Genetics and Cytogenetics 2, 139-143 (1980) 52 Vandarbilt Ave., New York, NY 10017 0165-4608/80/04013905502.25

1 3 9

140 F. Carbonell, E. Kratt, and K. Neuhaus

MATERIAL AND METHODS

Chromosome anlayses were performed from bone marrow cells with the direct tech- nique. Peripheral blood leukocytes were cultured with human placenta conditioned medium as the source of colony stimulating activity (CSA) for 48 hr and with phyto- hemagglutinin (PHA) for 72 hr. Cytogenetic studies were made using the G-banding technique [21].

Figure 1 Karyotype of the abnormal cell clone.

t

1 2 3

6, 8 9 10 11 12 7

14 13 15 16 17 18

19 20 21 22

141

A A

°

( l II I . 6 61)+ 9 9q4. 11 11q- 22 I~

Figure 2 Partial karyotype from three cells and schematic representation of the complex translocation.

142 F. Carbonell, E. Kratt, and K. Neuhaus

RESULTS AND DISCUSSION

All 40 bone marrow metaphases showed a Ph 1, but it was not possible to analyze the metaphase with the banding technique.

However, in the blood leukocyte cultures with CSA as a "growth factor," an ab- normal cell clone with a rearrangement of four chromosomes: 46,XX,t(6;9;22;11) was observed in all 28 metaphases analyzed. The fragment missing on the long arm of chromosome #11 is attached to the short arm of chromosome #6. The short arm of chromosome #6 is attached to the long arm of the chromosome #9. The fragment missing on one of the #22 chromosomes (Ph 1) is attached on the long arm of chromo- some #11 (Figs. 1 and 2). Only one karyotype from the culture of blood cells with PHA showed the abnormal clone, the ather 19 cells analyzed presented a normal karyotype.

The clinical and laboratory data of this patient does not differ from the 36 cases of CML with t(9;22) that were studied in our laboratory. Our observation is compatible with the results reported in a recent review by Sonta and Sandberg [20]. These au- thors analyzed 30 patients with unusual and complex translocations and did not find any significant difference in the clinical features and prognosis of these cases com- pared with those CML patients wi th the more commonly observed Ph 1 translocation.

Research supported by the Deutsche Forschungsgemeinschaft and the European Atomic Energy Community (Euratom).

REFERENCES

1. Canellos GP, Whang-Peng J, DeVita VT (1976): Chronic granulocytic leukemia without the Philadelphia chromosome. Am J Clin Pathol 65,467 -470.

2. Hossfeld DK (1975): Chronic myelocytic leukemia: cytogenetic findings and their relations to pathogenesis and clinic. Ser Haematol 8, 53 - 72.

3. Sandberg AA, Hossfeld DK (1974): Chromosomal changes in human tumors and leukemias. In: Handbuch der Allgemeinen Pathologie, vol 6. Springer, Berlin, pp. 141 - 287.

4. Rowley JD (1973): A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 243, 290-293.

5. Berger R, Gyger M. Bussel A (1976): Anomalie chromosomique nouvelle dans une leucemie myeloide chronique. Nouv Rev Fr Hematol 16, 309- 320.

6. Berger R, Bernheim A (1978): Non-randomness in complex translocations of chronic myl eloid leukaemmia. Scand J Haematol 21,418-420.

7. Francesconi D, Pasquali F (1978): Three chromosomes (7;9;22) rearrangement and the origin of the Philadelphia chromosome. Hum Genet 43, 133 - 137.

8. Gahrton G, Friberg K, Zech L (1977): A new translocation involving three chromosomes in chronic myelocytic leukemia, 46,XY,t(9;11;22). Cytogenet Cell Genet 18, 75-81.

9. Hayata I, Sakurai M, Kakati S, Sandberg AA (1975): Chromosomes and causation of human cancer and leukemia. XVI: Banding studies of chronic myelocytic leukemia including five unusual Ph ~ translocations. Cancer 36, 1177-1191.

10. Hayata I, Sasaki M (1976): A case of Phi-positive chronic myelocytic leukemia associated with complex translocation. Proc Jap Acad 52, 29-32.

11. Lawler SD, O'Malley F, Lobb DS (1976): Chromosome banding studies in Philadelphia chro- mosome positive myeloid leukemia. Scand J Haematol 17, 17- 28.

12. Nowel! P, Jensen J, Gardner F (1975): Two complex translocations in chronic granulocytic leukemia involving chromosomes 22, 9 and a third chromosome. Humangentik 30, 13 - 21.

13. Potter AM, Sharp JC, Brown MJ, Sokol RJ (1975): Structural rearrangements associated with the Ph ~ chromosome in chronic granulocytic leukaemia. Humangenetik 29, 223-228.

C o m p l e x T r a n s l o c a t i o n i n CML 1 4 3

14. Rozynkowa D, Stepien J, Kowalenski J, Nowakowski A (1977): Non random chromosome rearrangements in 27 cases of human myeloid leukemia. Hum Genet 39,293 - 301.

15. Seabright M, Pearson J (1978): Cytogenetic finding in 108 cases of chronic myeloid leuke- mia. Clin Genet 14, 308- 309.

16. Verma RS, Dorik H (1977): The value of reverse banding in detecting bone marrow chromo- somal abnormalities: translocation between chromosomes 1, 9 and 22 in a case of chronic myelogenous leukemia (CML). Am J Hematol 3, 171-175.

17. First International Workshop on Chromosomes in Leukaemia (1978): Chromosomes in Ph t- positive chronic granulocytic leukemia. Br J Haematol 39, 305-309.

18. Mitelman F, Levan G (1978): Clustering of aberrations to specific chromosomes in human neoplasms. III. Incidence and geographic distribution of chromosome aberration in 856 cases. Hereditas 89, 207-232.

19. Pasquali F, Casalone R, Francesconi D, Peretti D, Fraccaro M, Bernasconi C, Lazzarino M (1979): Transposition of 9q34 and 22 (q11--~qter) regions has a specific role in chronic mye- locytic leukemia. Hum Genet 52, 5 5 - 67.

20. Sonta S, Sandberg AA (1977): Chromosomes and causation of human cancer and leukaemia: XXIV. Unusual and complex Ph I translocations and their clinical significance. Blood 50, 691-697.

21. Seabright M (1971): A rapid banding technique for human chromosomes. Lancet 2, 971-972.