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Erythroblastic transformation of Philadelphia chromosome (Ph1)-positive chronic myelogenous leukemia associated with marked chromosomal rearrangements
Erythroblastic Transformation of Philadelphia Chromosome (Ph1)-positive Chronic Myelogenous Leukemia Associated With Marked Chromosomal Rearrangements Naoki Sadamori, Shuichi Ikeda, Takaya Muta, Michito Ichimaru, and Masako Matsunaga
ABSTRACT:
In a 22-year-old female with Philadelphia chromosome (Phl)-pasitive chranic myeloge-
n o u s leukemia (CML) a t u m o r consisting of megaloblastic proerythroblasts appeared in the rig ht ilia-femoral region 2 years and 8 m o n t h s after the diagnosis of the disease and was treated effectively with irradiation. She developed erythroblastic transformation 3 months after the t u m o r appeared. Cytogenetic study of the bone marrow cells in the acute phase revealed marked chromosomal rearrangements such as ring, dicentric, or tricentric chromosomes.
INTRODUCTION
It is well k n o w n that blastic cells appearing in the acute p h a s e of chronic myelogenous leukemia (CML) show heterogeneity in a n u m b e r of parameters [1]. In addition, though most of cases with CML undergo an acute myeloblastic transformation, some CML cases m a y terminate in l y m p h o b l a s t i c [2,3], megakaryoblastic [4], or erythroblastic transformation [5,6,7]. Even though some chromosomal findings, using conventional staining methods, in erythroblastic transformation of the disease have been reported [5,6], there have been no reports using banding techniques. CASE REPORT
A 22-year-old female was seen initially in May 1973 with a 5 m o n t h history of abd o m i n a l fullness caused by marked splenomegaly. Hematological findings were hemoglobin 8.2 g/dl, WBC 202,200/mm 3 with a "left-shift" in the peripheral blood smear, and platelets 375,000/mm 3. The leukocyte alkaline p h o s p h a t a s e level was very low. The myeloid-to-erythroid (M:E) ratio in the bone marrow was 100:1. With the diagnosis of CML established, the a d m i n i s t r a t i o n of small doses of carboquone or busulfan was started. The patient did well until January 1976 w h e n a painful hard
From the Department of Hematology, Atomic Disease Institute, Nagasaki University School of Medicine, Nagasaki, Japan and St. Mary's Hospital, Fukue, Japan.
Address requests for reprints to Naaki Sadamori, M.D., Department of Hematology, Atomic Disease Institute, Nagasaki University School of Medicine, 7-1 Sakamoto-machi, Nagasaki 852, Japan. Received July 14, 1980; accepted November 13, 1980.
353 © Elsevier North Holland, Inc., 1981 52 Vanderbilt Ave., New York, NY 10017
Cancer Genetics and Cytogenetics 3, 353-357 (1981) 0165-4608/81/043530552.50
354
N. Sadamori et al. ,m
Figure 1
Bone marrow film showing megaloblastic proerythroblasts.
tumor a p p e a r e d in the right ilio-femoral region; the tumor was resistant to 6-mercaptopurine therapy. She was treated with irradiation (a total of 3000R) to the tumor in March 1976, with w h i c h the tumor size and pain were r e d u c e d considerably. In April 1976 an increasing n u m b e r of megaloblastic proerythroblasts a p p e a r e d in the peripheral blood; bone marrow aspirate revealed a relative erythroid hyperplasia (38.2%) including 8.4% of megaloblastic proerythroblasts (Fig. 1), 30% of the latter being PAS-(granular) positive. There was no increase in the number of immature l y m p h o i d cells or myeloblasts (3.4%) in the bone marrow. She died of s u d d e n heart failure 5 days after the blastic crisis. At autopsy, a touch preparation and section of the tumor in the right ilio-femoral region revealed extensive infiltration with megaloblastic proerythroblasts. The spleen and liver weighed 2250 and 2000 g, respectively. CYTOGENETIC STUDY The chromosomes were studied on direct preparations of the bone marrow. For chromosome banding studies, Q [8] and G banding [9] were used. Cytogenetic studies in February 1976, w h e n the tumor appeared in the right ilio-femoral region and no hematological blastic crisis occurred, as well as the studies in May 1973 and in August 1974, showed no additional changes besides the Ph I chromosome, with evidence of translocation between chromosomes #9 and #22. In April 1976 when erythroblastic transformation occurred, marked numerical and structural abnormalities, as given in Table 1, were revealed to be present. One of the metaphases (cell No. 12) is shown in Fig. 2. The chromosome numbers ranged from 43 to 46. Of 25 analyzable karyotypes, 20 (cells No. 6 - 25) were different from cell to cell (multiple abnormalities); most of them were h y p o d i p l o i d and had one or more structural rearrangements such as ring, dicentric or tricentric chromosomes. M o n o s o m y of chromosomes #5, #7, #10, #17, #19, and #22, a missing X, 5p+, 14q÷, and two kinds of marker chro-
Ph' CML Erythroblastic Crisis and Markers
Table 1
355
Cytogenetic findings in bone marrow cells in erythroblastic transformation of CML
Cell
Karyotype
1- 5 6 7 8 9 10 11 12 13 14 15 16 1~ 18 19 20 21 22 23 24 25
46,XX,t(9q+;22q--) 46,XX,8q--,t(9q +;22q--) 46,XX,--7,+marA,a5p+,14q+,t(9q+;22q - ) 46,XX,--5,--10, +marA, +marB,O14q+,t(9q +;22q- ) 45,XX,-19,t(9q +;22q--) 45,XX,-7,-14,+marA,t(9q+;22q-) 45,XX,-2,-10, +marC,Ct(9q+;22q- ) 45,X,-X,-16,-19, ÷marB, +marB,5p ÷,t(9q +;22q--) 45,XX,--17,-17, +marA,t(2q-;5p +),14q+,t(9q +;22q-) 44,XX,--17,-18,14q +,t(9q +;22q--) 44,XX,--5,-19,--22, +marB,t(9q +;22q--) 44,X,--X,-5,--17, +marB,t (9q +;22q--) 44,XX,--5,-17,-20, +marB,5p +,t(9q +;22q--) 44,X,--X,--5,--21, +marB,5p +,r(17),t(9q +;22q--) 44,XX,-7,--8,-9, +marA,i(llq),t(9q+;22q--) 44,XX,-8,--9,,--10, ÷marB, 14q+,22q44,XX,--7,--17,--22, +marA,9q +, 14q + 44,X,--X,--21,--22, +marD,O5p+,9q + 43,XX,--11,--16,-18,--22,÷marC,+marC,9q+,14q+ 43,XX,-7,-14,-19,-22, +marA,5p ÷,9q+,14q÷ 43,X,-X,-7,-17,--19,-22, +marA, +marA,5p +,9q+,14q+
"marA:markerchromosomelike chromosome#2. t'marB:ring chromosomeas shownin Fig. 2. CmarC:dicentriclargemarkerchromosome. OmarD:tricentriclargemarkerchromosome.
mosomes (ring and dicentric chromosomes) were c o m m o n to more than three cells, Five karyotypes (cells No. 21 -25) did not contain a Ph I chromosome, but a 9 q + was seen in each metaphase, which seemed to be evidence of a translocation between chromosomes # 9 and #22. Therefore, it is possible that these Ph'-negative cells had been derived from Ph'-positive cells in the chronic phase of the disease.
DISCUSSION The findings on May-Griinwald-Giemsa stained preparations and the PAS reaction ot the case presented are consistent with an erythroblastic transformation of CML. A tumor in the right ilio-femoral region appeared characterized by megaloblastic proerythroblasts, 3 months before the blastic crisis supervened. These findings suggest that the primary origin of the blastic crisis was in an extramedullary tissue, as described by other investigators [10,11]. Cytogenetic analysis of the bone marrow cells in the acute phase using banding techniques revealed h y p o d i p l o i d y and marked structural rearrangements. According to the results obtained at the First International Workshop on Chromosomes in Leukemia [12], hypodiploidy, as in this patient, is an extremely rare occurrence, being observed in less than 1% of CML cases. Rosenthal et al. [5] reported also a case oi erythroblastic transformation of CML with a hypodiploid karyotype (45, phi). This patient's karyotype was characterized by marked structural changes, consisting of ring, dicentric or tricentric chromosomes; these changes probably made replication difficult at a selective advantage in the bone marrow. Inasmuch as karyo-
356
N. Sadamori
et
al.
Figure 2 Q-banding metaphase from bone marrow cell (cell No. /2) in erythroblastic transformation. Arrows point to the two ring markers, 5p÷, 9q÷, and PhL
types differed from cell to cell and so many chromosomes were ill-defined, conclusive d o c u m e n t a t i o n of break points and origins of these markers was difficult. Srodes et al. [6] described a case of erythroblastic transformation of CML with a ring chromosome. Whether these marked chromosomal rearrangements in our patient were induced by therapeutic irradiation to the extramedullary tumor or were associated with the erythroblastic changes is u n k n o w n . It is probably unlikely that irradiation would lead to clones with marked chromosomal abnormalities in only one month. Another 57-year-old male with CML terminating in an erythroblastic transformation, whose case report will be published elsewhere, showed 61 chromosomes with three rearranged marker chromosomes (61,XY,÷3,÷4,÷5,÷6,÷8,÷10,÷10,÷13,÷14, ÷18,÷19,÷Phl,÷M,,÷M~,÷M3,t(9q÷;22q--)) in the bone marrow cells and had no history of therapeutic irradiation. These experiences may incline one to think that marked karyotypic abnormalities in erythroblastic transformation are due to the erythroblastic condition rather than a result of irradiation. It is significant to note that major karyotypic abnormalities (MAKA), like those in the CML patients reported, have been described in erythroleukemic cases, as well as in acute myelogenous leukemia, without a history of therapeutic irradiation, as reported by Sakurai and Sandberg [13]. Nevertheless, in this CML patient the possibility of irradiation i n d u c i n g the cytogenetic changes cannot be excluded; unfortunately, no cytogenetic studies of bone marrow cells or extramedullary tissue were done in March prior to the radiation treatment. We would like to express our appreciation to Drs. Yu Tomonaga, Masuko Tagawa, Miyuki Kusano, Kenji Nishino, and Eiichi Yao, all of the Cytogenetic Study Group, Department of Hema-
P h ~ CML E r y t h r o b l a s t i c Crisis a n d M a r k e r s
357
tology, Atomic Disease Institute, Nagasaki University School of Medicine, for their chromosomal analysis.
REFERENCES 1. Shaw MT, Bottomley RH, Grozea PN, Nordquist RE (1975): Heterogeneity of morphological, cytochemical, and cytogenetic features in the blastic phase of chronic granulocytic leukemia. Cancer 35,199 - 207. 2. Boggs DR (1974): Editorial: Hematopoietic stem cell theory in relation to possible lymphoblastic conversion of chronic myeloid leukemia. Blood 44, 449 - 453. 3. Janossy G, Greaves MF, Sutherland R, Durrant J, Lewis C (1977): Comparative analysis of membrane phenotypes in acute lymphoid leukaemia and in lymphoid blast crisis of CML. Leukemia Res 1,289 - 300. 4. Hossfeld DK, Tormey D, Ellison RR (1975): Ph'-positive megakaryoblastic leukemia. Cancer 36,576- 581. 5. Rosenthal S, Canellos GP, Gralnick HR (1977): Erythroblastic transformation of chronic granulocytic leukemia. Am J Med 63,116-124. 6. Srodes CH, Hyde EF, Pan SF, Chervenick PA, Boggs DR (1973): Cytogenetic studies during remission of blastic crisis in a patient with chronic myelocytic leukaemia. Scand J Haematol 10, 130-135. 7. Scott RB, Ellison RR, Ley AB (1964): A clinical study of twenty cases of erythroleukemia (di Guglielmo's syndrome). Am J Med 37,162 - 171. 8. Caspersson T, Zech L, Johansson C (1970): Differential banding of alkylating fluorochromes in human chromosomes. Exp Cell Res 60,315 - 319. 9. Sumner AT, Evans HJ, Buckland RA (1971): New techniques for distinguishing human chromosomes. Nature 232, 31 - 32. 10. Spiers ASD, Baikie AG (1968): Cytogenetic evolution and clonal proliferation in acute transformation of chronic granulocytic leukaemia. Br J Cancer 22,192. 11. Stoll C, Oberling F, Flori E (1978): Chromosome analysis of spleen and/or lymph nodes of patients with chronic myeloid leukemia (CML). Blood 52,828-838. 12. First International Workshop on Chromosomes in Leukaemia (1978): Chromosomes in Ph'positive chronic granulocytic leukaemia. Br J Haemat 39, 305 - 309. 13. Sakurai M, Sandberg AA (1976): Chromosomes and causation of human cancer and leukemia. XIII. An evaluation of karyotypic findings in erythroleukemia. Cancer 37, 790-804.
ABSTRACT:
In a 22-year-old female with Philadelphia chromosome (Phl)-pasitive chranic myeloge-
n o u s leukemia (CML) a t u m o r consisting of megaloblastic proerythroblasts appeared in the rig ht ilia-femoral region 2 years and 8 m o n t h s after the diagnosis of the disease and was treated effectively with irradiation. She developed erythroblastic transformation 3 months after the t u m o r appeared. Cytogenetic study of the bone marrow cells in the acute phase revealed marked chromosomal rearrangements such as ring, dicentric, or tricentric chromosomes.
INTRODUCTION
It is well k n o w n that blastic cells appearing in the acute p h a s e of chronic myelogenous leukemia (CML) show heterogeneity in a n u m b e r of parameters [1]. In addition, though most of cases with CML undergo an acute myeloblastic transformation, some CML cases m a y terminate in l y m p h o b l a s t i c [2,3], megakaryoblastic [4], or erythroblastic transformation [5,6,7]. Even though some chromosomal findings, using conventional staining methods, in erythroblastic transformation of the disease have been reported [5,6], there have been no reports using banding techniques. CASE REPORT
A 22-year-old female was seen initially in May 1973 with a 5 m o n t h history of abd o m i n a l fullness caused by marked splenomegaly. Hematological findings were hemoglobin 8.2 g/dl, WBC 202,200/mm 3 with a "left-shift" in the peripheral blood smear, and platelets 375,000/mm 3. The leukocyte alkaline p h o s p h a t a s e level was very low. The myeloid-to-erythroid (M:E) ratio in the bone marrow was 100:1. With the diagnosis of CML established, the a d m i n i s t r a t i o n of small doses of carboquone or busulfan was started. The patient did well until January 1976 w h e n a painful hard
From the Department of Hematology, Atomic Disease Institute, Nagasaki University School of Medicine, Nagasaki, Japan and St. Mary's Hospital, Fukue, Japan.
Address requests for reprints to Naaki Sadamori, M.D., Department of Hematology, Atomic Disease Institute, Nagasaki University School of Medicine, 7-1 Sakamoto-machi, Nagasaki 852, Japan. Received July 14, 1980; accepted November 13, 1980.
353 © Elsevier North Holland, Inc., 1981 52 Vanderbilt Ave., New York, NY 10017
Cancer Genetics and Cytogenetics 3, 353-357 (1981) 0165-4608/81/043530552.50
354
N. Sadamori et al. ,m
Figure 1
Bone marrow film showing megaloblastic proerythroblasts.
tumor a p p e a r e d in the right ilio-femoral region; the tumor was resistant to 6-mercaptopurine therapy. She was treated with irradiation (a total of 3000R) to the tumor in March 1976, with w h i c h the tumor size and pain were r e d u c e d considerably. In April 1976 an increasing n u m b e r of megaloblastic proerythroblasts a p p e a r e d in the peripheral blood; bone marrow aspirate revealed a relative erythroid hyperplasia (38.2%) including 8.4% of megaloblastic proerythroblasts (Fig. 1), 30% of the latter being PAS-(granular) positive. There was no increase in the number of immature l y m p h o i d cells or myeloblasts (3.4%) in the bone marrow. She died of s u d d e n heart failure 5 days after the blastic crisis. At autopsy, a touch preparation and section of the tumor in the right ilio-femoral region revealed extensive infiltration with megaloblastic proerythroblasts. The spleen and liver weighed 2250 and 2000 g, respectively. CYTOGENETIC STUDY The chromosomes were studied on direct preparations of the bone marrow. For chromosome banding studies, Q [8] and G banding [9] were used. Cytogenetic studies in February 1976, w h e n the tumor appeared in the right ilio-femoral region and no hematological blastic crisis occurred, as well as the studies in May 1973 and in August 1974, showed no additional changes besides the Ph I chromosome, with evidence of translocation between chromosomes #9 and #22. In April 1976 when erythroblastic transformation occurred, marked numerical and structural abnormalities, as given in Table 1, were revealed to be present. One of the metaphases (cell No. 12) is shown in Fig. 2. The chromosome numbers ranged from 43 to 46. Of 25 analyzable karyotypes, 20 (cells No. 6 - 25) were different from cell to cell (multiple abnormalities); most of them were h y p o d i p l o i d and had one or more structural rearrangements such as ring, dicentric or tricentric chromosomes. M o n o s o m y of chromosomes #5, #7, #10, #17, #19, and #22, a missing X, 5p+, 14q÷, and two kinds of marker chro-
Ph' CML Erythroblastic Crisis and Markers
Table 1
355
Cytogenetic findings in bone marrow cells in erythroblastic transformation of CML
Cell
Karyotype
1- 5 6 7 8 9 10 11 12 13 14 15 16 1~ 18 19 20 21 22 23 24 25
46,XX,t(9q+;22q--) 46,XX,8q--,t(9q +;22q--) 46,XX,--7,+marA,a5p+,14q+,t(9q+;22q - ) 46,XX,--5,--10, +marA, +marB,O14q+,t(9q +;22q- ) 45,XX,-19,t(9q +;22q--) 45,XX,-7,-14,+marA,t(9q+;22q-) 45,XX,-2,-10, +marC,Ct(9q+;22q- ) 45,X,-X,-16,-19, ÷marB, +marB,5p ÷,t(9q +;22q--) 45,XX,--17,-17, +marA,t(2q-;5p +),14q+,t(9q +;22q-) 44,XX,--17,-18,14q +,t(9q +;22q--) 44,XX,--5,-19,--22, +marB,t(9q +;22q--) 44,X,--X,-5,--17, +marB,t (9q +;22q--) 44,XX,--5,-17,-20, +marB,5p +,t(9q +;22q--) 44,X,--X,--5,--21, +marB,5p +,r(17),t(9q +;22q--) 44,XX,-7,--8,-9, +marA,i(llq),t(9q+;22q--) 44,XX,-8,--9,,--10, ÷marB, 14q+,22q44,XX,--7,--17,--22, +marA,9q +, 14q + 44,X,--X,--21,--22, +marD,O5p+,9q + 43,XX,--11,--16,-18,--22,÷marC,+marC,9q+,14q+ 43,XX,-7,-14,-19,-22, +marA,5p ÷,9q+,14q÷ 43,X,-X,-7,-17,--19,-22, +marA, +marA,5p +,9q+,14q+
"marA:markerchromosomelike chromosome#2. t'marB:ring chromosomeas shownin Fig. 2. CmarC:dicentriclargemarkerchromosome. OmarD:tricentriclargemarkerchromosome.
mosomes (ring and dicentric chromosomes) were c o m m o n to more than three cells, Five karyotypes (cells No. 21 -25) did not contain a Ph I chromosome, but a 9 q + was seen in each metaphase, which seemed to be evidence of a translocation between chromosomes # 9 and #22. Therefore, it is possible that these Ph'-negative cells had been derived from Ph'-positive cells in the chronic phase of the disease.
DISCUSSION The findings on May-Griinwald-Giemsa stained preparations and the PAS reaction ot the case presented are consistent with an erythroblastic transformation of CML. A tumor in the right ilio-femoral region appeared characterized by megaloblastic proerythroblasts, 3 months before the blastic crisis supervened. These findings suggest that the primary origin of the blastic crisis was in an extramedullary tissue, as described by other investigators [10,11]. Cytogenetic analysis of the bone marrow cells in the acute phase using banding techniques revealed h y p o d i p l o i d y and marked structural rearrangements. According to the results obtained at the First International Workshop on Chromosomes in Leukemia [12], hypodiploidy, as in this patient, is an extremely rare occurrence, being observed in less than 1% of CML cases. Rosenthal et al. [5] reported also a case oi erythroblastic transformation of CML with a hypodiploid karyotype (45, phi). This patient's karyotype was characterized by marked structural changes, consisting of ring, dicentric or tricentric chromosomes; these changes probably made replication difficult at a selective advantage in the bone marrow. Inasmuch as karyo-
356
N. Sadamori
et
al.
Figure 2 Q-banding metaphase from bone marrow cell (cell No. /2) in erythroblastic transformation. Arrows point to the two ring markers, 5p÷, 9q÷, and PhL
types differed from cell to cell and so many chromosomes were ill-defined, conclusive d o c u m e n t a t i o n of break points and origins of these markers was difficult. Srodes et al. [6] described a case of erythroblastic transformation of CML with a ring chromosome. Whether these marked chromosomal rearrangements in our patient were induced by therapeutic irradiation to the extramedullary tumor or were associated with the erythroblastic changes is u n k n o w n . It is probably unlikely that irradiation would lead to clones with marked chromosomal abnormalities in only one month. Another 57-year-old male with CML terminating in an erythroblastic transformation, whose case report will be published elsewhere, showed 61 chromosomes with three rearranged marker chromosomes (61,XY,÷3,÷4,÷5,÷6,÷8,÷10,÷10,÷13,÷14, ÷18,÷19,÷Phl,÷M,,÷M~,÷M3,t(9q÷;22q--)) in the bone marrow cells and had no history of therapeutic irradiation. These experiences may incline one to think that marked karyotypic abnormalities in erythroblastic transformation are due to the erythroblastic condition rather than a result of irradiation. It is significant to note that major karyotypic abnormalities (MAKA), like those in the CML patients reported, have been described in erythroleukemic cases, as well as in acute myelogenous leukemia, without a history of therapeutic irradiation, as reported by Sakurai and Sandberg [13]. Nevertheless, in this CML patient the possibility of irradiation i n d u c i n g the cytogenetic changes cannot be excluded; unfortunately, no cytogenetic studies of bone marrow cells or extramedullary tissue were done in March prior to the radiation treatment. We would like to express our appreciation to Drs. Yu Tomonaga, Masuko Tagawa, Miyuki Kusano, Kenji Nishino, and Eiichi Yao, all of the Cytogenetic Study Group, Department of Hema-
P h ~ CML E r y t h r o b l a s t i c Crisis a n d M a r k e r s
357
tology, Atomic Disease Institute, Nagasaki University School of Medicine, for their chromosomal analysis.
REFERENCES 1. Shaw MT, Bottomley RH, Grozea PN, Nordquist RE (1975): Heterogeneity of morphological, cytochemical, and cytogenetic features in the blastic phase of chronic granulocytic leukemia. Cancer 35,199 - 207. 2. Boggs DR (1974): Editorial: Hematopoietic stem cell theory in relation to possible lymphoblastic conversion of chronic myeloid leukemia. Blood 44, 449 - 453. 3. Janossy G, Greaves MF, Sutherland R, Durrant J, Lewis C (1977): Comparative analysis of membrane phenotypes in acute lymphoid leukaemia and in lymphoid blast crisis of CML. Leukemia Res 1,289 - 300. 4. Hossfeld DK, Tormey D, Ellison RR (1975): Ph'-positive megakaryoblastic leukemia. Cancer 36,576- 581. 5. Rosenthal S, Canellos GP, Gralnick HR (1977): Erythroblastic transformation of chronic granulocytic leukemia. Am J Med 63,116-124. 6. Srodes CH, Hyde EF, Pan SF, Chervenick PA, Boggs DR (1973): Cytogenetic studies during remission of blastic crisis in a patient with chronic myelocytic leukaemia. Scand J Haematol 10, 130-135. 7. Scott RB, Ellison RR, Ley AB (1964): A clinical study of twenty cases of erythroleukemia (di Guglielmo's syndrome). Am J Med 37,162 - 171. 8. Caspersson T, Zech L, Johansson C (1970): Differential banding of alkylating fluorochromes in human chromosomes. Exp Cell Res 60,315 - 319. 9. Sumner AT, Evans HJ, Buckland RA (1971): New techniques for distinguishing human chromosomes. Nature 232, 31 - 32. 10. Spiers ASD, Baikie AG (1968): Cytogenetic evolution and clonal proliferation in acute transformation of chronic granulocytic leukaemia. Br J Cancer 22,192. 11. Stoll C, Oberling F, Flori E (1978): Chromosome analysis of spleen and/or lymph nodes of patients with chronic myeloid leukemia (CML). Blood 52,828-838. 12. First International Workshop on Chromosomes in Leukaemia (1978): Chromosomes in Ph'positive chronic granulocytic leukaemia. Br J Haemat 39, 305 - 309. 13. Sakurai M, Sandberg AA (1976): Chromosomes and causation of human cancer and leukemia. XIII. An evaluation of karyotypic findings in erythroleukemia. Cancer 37, 790-804.