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A t(3;5) in blastic phase of a Philadelphia chromosome-negative chronic myeloid leukemia
A t(3;5) in Blastic Phase of a Philadelphia Chromosome-Negative Chronic Myeloid Leukemia M. De Braekeleer and M. Vekemans
ABSTRACT: Serial cytogenetic analyses from the bone marrow of a patient with blastic phase of a
Philadelphia chromosome-negative chronic myeloid leukemia revealed a t(3;5)(p21 ;q31). The literature on translocations involving chromosome 3 and the long arm of chromosome 5 is reviewed. The importance of breakpoints in band 5q31 is discussed.
INTRODUCTION
Chromosome abnormalities in nonlymphocytic leukemia have been much studied. Correlations between some chromosome abnormalities and the morphology of blast cells and/or the clinical course of the disease were found by several groups [1, 2]. Translocations involving chromosome 3 and the long arm of chromosome 5 have been reported in several cases of acute nonlymphocytic leukemia (ANLL) and myelodysplastic syndromes (MDS) [3-20]. We report here a further case in which a t(3;5)(p21;q31) arose in the setting of blastic phase of a Philadelphia (Ph) chromosome-negative chronic myeloid leukemia (CML).
CASE REPORT
The patient, a 17-year-old man, was first seen for Ph-negative CML in transition. At that time he was treated with hydroxyurea, which brought his white blood cell count (WBC) from 115 x 109/L down to 12 x 109/L. A week later, the WBC was at 18.5 x 109/L with 48% blasts, 2% metamyelocytes, 22% polymorphnnucleocytes, and 28% granulocytes. A diagnosis of blastic phase was made and chemotherapy i n c l u d i n g d a u n o m y c i n and cytosine arabinoside was started. A complete remission was achieved 3 weeks later and maintenance therapy was begun. Relapse occurred 23 months later. The WBC was at 1.4 x 10~/L with 13% blasts, hemoglobin was 9.8 g/dl, and platelets were 16 x 109/L. The bone marrow aspirate showed 33°/,, undifferentiated blasts. Complete remission was achieved 1 week later. The patient experienced a second relapse 8 months later. The bone marrow aspirate showed 30% myeloid blasts with maturation (FAB type m2). The WBC was 0.9 x 109/L with 14% blasts, and platelets were 23 x 109/L. The clinical course was then complicated by recurrent From SOREP, Departmentof Human Sciences, Universityof QuelM;cat Chicoutimi.Chicoutinli(M. D.) and the Departmentof Pediatric Pathology, MontrealChildren's I[ospital.Montreal (M. V.). Quebec.Canada. Address reprint requests to: Dr. M. De lIraekeleer. SOREP, Universityof Quebec at Chicautimi. 555 Boulevard de l'Universite, Chicoutimi. Quebec G711 2B1, Canada. Received April 29, 1988: accepted September 23, 1988.
163 © 1989 Elsevier SciencePublishingCo., Inc.
Cancer Genet Cytogenet37:163-168 (1989]
655 Avenueof the Americas,New York, NY 10010
0165-4608/89/S03.50
164
M. De Braekeleer and M. Vekemans infections and thrombocytopenia requiring frequent platelet transfusions. The patient is still in blastic phase. His last WBC was 59.4 x 109/L with 44% blasts, hemoglobin was 9.5 g/dl, and platelets were 19 x 109/L.
CYTOGENETIC STUDIES Serial cytogenetic analyses were performed on bone marrow cells immediately after collection and/or after 24- and 48-hour cultures with or without methotrexate and on peripheral blood cell cultures for 24 hours without phytohemagglutinin. G banding was performed by the trypsin-Giemsa method (GTG), and the karyotypes were arranged according to the recommendations of the [SCN [21]. An initial cytogenetic analysis of blood cells performed on April 9, 1984, showed a normal mate karyotype (18 cells). The analysis performed on April 30, 1984, when the patient was in blastic phase, showed the presence of a t(3;5)(p21;q31) in the 20 bone marrow cells examined (Fig. 1). The analysis was repeated when the patient -was in complete remission, and a normal karyotype was found at that time. No analysis was done at first relapse. At second relapse, the karyotype again showed the t(3;5)(p21;q31) without any additional abnormalities.
Figure I
G-bandedkaryotype showing the t(3;5)(p21;q31).
165
t(3;5) in Ph-Negative CML Table 1
Patients w i t h a t(3;5)-associated n o n l y m p h o c y t i c l e u k e m i a or myelodysplastic syndrome
Reference
Type of leukemia
Sex/age
[3]
M/45
Ph+CML in BP
[41
F/65
AML
[5] [61 [7]
[81 [9] [10]
F/23 F/47 F M M F/20 M/55 M/71
M2 foil MDS M6 M2 M2 M2 M4 M6 RAEB
Ill]
M/60
M4
[12] [13] [14]
M/32 M/21 F/65
M4 M4 M6
[15] [16] [17] [18] [19]
M/38 M/40 F/36 F/32 M/17
RA-M2 M4 M2 M2 Ph+CML Ph~-CML in BP
[201 Present study
F/7 M/16 M/17
M2 M5b Ph-CML in BP
Karyotype 46,XY,t(4;22)(q35;q11),t(3;5)(q27;q22), i( 17q)/50,XY,t(4; 22) ,t(3;5), + 8, + 15, + 21, + Ph ,i (17q)/50,XY,t[4:22),t(3 ;5), + 15, + 21, + Ph,i(17q), + mar 47,X,Xq-,-3,* t(3;5),- 5,- 5,- 11,+t(11;?), - 12,+t(12;17),- 17,- 18,-21,+ 6mar 46,XX,t(3;5)(q21;q31) 46,XX,t(3;5)(q21;q31) 46,XX,t(3;5)(q25;q31) 46,XY,t(3;5)(q24;q34) 46,XY,t(3;5)(q21;q31) 46,XX,t(3;5)(q26;q31) 46,XY,t(3;5)(q13;q23) 48,XY,+ 8, + ~1~,t(3;5)(pl 3:q13)/48,XY,+ 8, t(3;5),t(6;l 3)(p25;qi 1 ),+ ?del(5)(q31q35) 42,XY,t(3;5)(qter;q13),t(7;12)(q12;q14), l(7;10)(q12;q21),- 8,- 17,- 18,- 20 46,XY,t(3;5)(q25;q33) 46,XY,t(3;5)(q25;q31or32) 47,XX,t(3;5)(q21;q31),- 1,- 13,+ 8,+22, + der(1)t(1;13)(p36:ql 4) 46,XY,t(3;5)(q21;q31) 46,XY,t(3;5)(q21;q31) 46,XX,t(3;5)(q21;q31) 46,XX,t[3;5)(q21;q31) 46,XY,t(9;22)(q34;q11)/47,XY,t(9;22), + Ph/46,XY,t(9;22),t(3p;5q),t(6p;13q) 46,XY,t(9;22 )/46,XY,t(9;22), + Ph,-9/ 46,XY,t(9;22),t(3p;5q),t(6p;13q) 46,XX,t(3;5)(q24;q32) 46,XY,t(3;5)(q24;q32) 46,XY,t(3;5)(p21;q31)
DISCUSSION With the d e v e l o p m e n t of criteria for MDS a n d myeloproliferative disorders, it has b e c o m e clear that Ph-negative CML represents a heterogeneous group of diseases [22, 23]. S t u d i e s have also s h o w n a subset of patients with Ph-negative CML w i t h a r e a r r a n g e m e n t of c-abl a n d bcr, as typically seen in Ph-positive CML [24-26]. W h e t h e r the p a t i e n t reported here belongs to that subset is not k n o w n as no DNA a n a l y s i s was done. It is, however, n o t i c e a b l e that the patient achieved two c o m p l e t e r e m i s s i o n s , o n e lasting 23 m o n t h s a n d the other 8 m o n t h s . T w e n t y - t w o patients with a n o n l y m p h o c y t i c l e u k e m i a associated with a t(3;5) have n o w b e e n reported [3-20] (Table 1). A t(3;5) i n v o l v i n g the long arm of c h r o m o some 5 was also reported in a case of h y p e r e o s i n o p h i l i a s y n d r o m e [27], a case of m y e l o m a [28], a n d a case of H o d g k i n ' s disease [29]. Therefore, it appears that translocations i n v o l v i n g c h r o m o s o m e 3 a n d the long arm of c h r o m o s o m e 5 are specific to n o n l y m p h o c y t i c l e u k e m i a a n d MDS, as are deletions of 5q [30]. A l t h o u g h the t(3;5) was recognized as a n e w cytogenetic entity at the F o u r t h I n t e r n a t i o n a l W o r k s h o p o n
166
M. De Braekeleer and M. Vekemans
3
5
I
1
1:
®
• 2
00
0
0000 0000 000 000 0 0
0 0
000000
|**°°
0
Figure 2 Breakpoint distribution in t(3:5) in nonlymohocytic leukemia and myelodyspiastic disorders.
Chromosomes in Leukemia in 1982 [5], this abnormality had already been reported by Golomb et al. and Oshimura et al. in ]976 [!2, 74]. The sex ratio is not distorted, being ] 3 males and 9 females. The age at onset varies from 7 to 71 years. Originally, it was thought that the t(3:5) could be specifically associated with ANLL-M2 when it was recognized as a distinct entity 15, 7, 18]. However, the distribution of the types of leukemia shows that the translocation can be found in all types of n e n l y m p h o c y t i c leukemia, as it has been reported in eight cases 9f M2, five cases of M4. one case of M5, and three cases of M~5. The abnormality has also been found in MDS [10, 15] and in Ph-positive or -negatiw,~ CMI, in chronic and blastic phases [3, 19: present case[. Because the clinical and laboratory data are still sparse, it is impossible to see whether the t{3;5) is associated with a specific clinical picture or if it carries a poor or a good prognosis. Figure 2 shows the breakpoint distribution on chromosome 3 and on the long arm of c h r o m o s o m e 5. The breakpoints on chromosome 3 are distributed in nine bands, with eight breaks being in band 3q21. Twelve of the 20 breakpoints occurring in the long arm of chromosome 5 were assigned to band 5q32. Therefore, although eight of the 20 translocations with identified breakpoints were reported as t(3;5)(q21;q31), the specific rearrangement appears to be a break in band 5q3]. The distal part of the long arm of chromosome 5 contains a family of genes regulating hemopoiesis [31]. The granulocyte-macrophage colony stimulating factor (GM-CSF} gene was localized at bands 5q23-q31, the macrophage colony stimulating factor (CSF-1) at band 5q33.1, and the protooncogene FMS at bands 5q33.2-33.3 [31]. It was also s h o w n that the protooncogene FMS encodes a protein that is related or possibly identical to the receptor for CFS-1 [321. Moreover, the gone encoding the c~adrenergic surface receptor was m a p p e d to band 5q35 [331, and the gene encoding the platelet-derived growth factor receptor to bands 5q31-q32 (Y. Yarden, quoted in [31]~:. Therefore, there is evidence that a functional family of genes that regulate the growth of hematopoietic cells maps to a restricted region of 5q. it also raises the possibility that genes encoding other growth factors and receptors may be located in
t(3;5) i n P h - N e g a t i v e CML
167
t h e s a m e region. W h e t h e r t h e b r e a k in 5q31, as r e c o r d e d in t h e t(3;5), i n d u c e s a c t i v a t i o n or i n a c t i v a t i o n of a g r o w t h factor or a g r o w t h factor r e c e p t o r r e m a i n s to b e determined.
REFERENCES 1. First International Workshop on Chromosomes in Leukemia (1978): Chromosomes in acute nonlymphocytic leukemia. Br J Haematol 39:311-316. 2. Fourth International Workshop on Chromosomes in I,eukemia, 1982 (1984): Clinical significance of chromosomal abnormalities in acute nonlymphoblastic leukemia. Cancer Gem:t Cytogenet ] ] :332-350. 3. Sessarego M, Pnarello C, Coviello DA, Boccaccio P, Ajmar F (1987): Karyotype evolution in CMI,: High frequency of translocations other than the Ph. Cancer Genet Cytogenet 25:73-80. 4. Pedersen-Bjergaard J, Haahr S, Philip P, Thomson M, Jensen G, Ersboll J, Nisse~l NI (1980): Abolished production of interferon hy leucocytes of patients with the acquired cytogenetic abnormalities 7 q - or - 7 in secondary and de-novo acute non lymphocytic leukemia. Br ] Haematol 46:211-223. 5. Pi D, Kalousek DK (1986): Translocation t(3:5) in acute myelocytic leukemia type M2. Cancer Goner Cytogenet 20:171. 6. Smadja N, Krulik M, de Gramont A, Sirinelli A, Dray C, Brissand P, Debray J [1986): Translocation t(3;5) and acute nonlymphocytic leukemia. Cancer Genet Cytogenet 20:173174. 7. Fourth International Workshop on Chromosomes in Leukemia, 1982 (1984): Abnormalities of chromosome 3 among 24 patients with de novo ANLL. Cancer Genet Cytogenet 11:306. 8. Prigogina EL, Fleischman EW, Puchkova GP, Mayakova SA, Volkova MA. Protasova AK, Frenkel MA (1986): Chromosomes in acute noulymphocytic leukemia. Hum Genet 73:137146. 9. Hagemeijer A, Hahlen K, Abels J [1981): Cytogenetic follow-up of patients with non-lymphocytic leukemia. II. Acute non-lymphocytic leukemia. Cancer Genet Cytagenet 3:109124. 10. Knapp RH, Dewald GW, Pierre RV (1985); Cytogenetic studies in 174 consecutive patients with pre]eukemia or myelodysplastic syndromes. Mayo Clin Proc 60:507-516. 11. Mitelman F, Nilsson PG, Brandt L, Alimena G, Gastoldi R, Dallapiccola B (1981): Chromosome pattern, occupation, and clinical features in patients with acute nonlymphocytic leukemia. Cancer (;enet Cytogenc't 4:197-214. 12. Golomb HM, Vardiman JW, Rowley JD (1976): Acute nonlymphocytic leukemia in adults: Correlations with Q-banded chromosomes. Blood 48:9-21. 13. Golomb HM, Alimena G, Rowley JD, Vardiman JW, Testa JR, Sovik C (19821: Correlation of occupation and karyotype in adults with acute nonlymphocytic leukemia. Blood 60:404411. 14. Oshimura M. Hayata I, Kakati S, Sandberg AA (1976): Chromosomes and causation of h u m a n cancer and leukemia. XVII. Banding studies in acute myeloblastic leukemia (AML). Cancer 38:748-761. 15. Sharp FC~, Robertson J, Heppleston AD (1987): t(3;5)(q21;q31) in a myelodysplastic syndrome. Leukemia Res 11:629-633. 16. Misawa S, Hogge DE, Oguma N. Wiernick PH, Testa JR (1986): Detection of clonal karyotypic abnormalities in most patients with acute nonlymphocytic leukemia examined using short-term culture techniques. Cancer Genet Cytogenet 22:239-251. 17. McCarthy CMT, Cobcroft RG, Harris MG, Scott DC (1987): Sweet's syndrome, acute hmkemia, and t(3:5). Cancer Genet Cytogenet 28:87-91. 18. Werner-Fabre C, Engel E, Beris P (1985): Translocation t(3;5] in ANLL. Cancer (;enet Cytogenet 16:279. 19. Kohno SI, Sandberg AA (1980): Chromosomes and causation of human cancer and leukemia. XXXIX. Usual and unusual findings in Ph-positive CML. Cancer 46:2227-2237. 20. Berger R, Bernheim A, Daniel M'F, Flandrin G (1987): Translocation t(3:5)(q24;q32) in two acute nonlymphocytic h.'ukemias. Cancer Genet Cytogenet 28:261-265.
168
M. De Braekeleer and M. V e k e m a n s
21. ISCN (1978): An International System for Human Cytogenetic Nomenclature (1978). Birth Defects: ()riginal Article Series. Vol. XIV, No. 8 (The National Foundation, New York, 1978}; also in Cytogenet Ce',l Genet 21:309-3C~4 (1978). 22. Pugh WC, Pearson M, Vardiman JW, Rowley JD (! 985): Philadelphia chromosome negative chronic myelogenous !eukemia: A morphological reassessment. 8r J Haematol 60:457-467. 23. Travis I,B, Pi,.'rre RV, De Wald GW (~.986): Ph negative chronic granulecytic hmkemia: A non-entity. Am I Clin Pathol 85:186-193. 24. Bar[ram CR, Ki~,ihauer E, de Klein A, Grosveld G, Teyssier IR, Heisterkanlp N, Greffen J ('-985): c-abl and bcr are rearranged ii'~ a Ph-negative CML patient. EMBO j 4:683-686. 25. Bartram CR, Carbonell F (1986): bc'r rearrangement in Ph-negative CMI,. Cancer Goner Cytogenet 21:183-184. 26. Morris CM, Reeve AE, Fitzgerald PH, Hollings PE, Beard MEJ, Heatnn D(" (1986): Genomic diversity correlates with clinical wtriation in Ph-negative chronic myeloid leukemia. Nature 320:281-283. 27. Bitran JD, Rowley JD, Plapp F, Golomb HM, Ultmann JE (1977): Chromosomal aneuploidy in a patient with hypereosinophilic syndrome. Evidence for a malignant disease. Am J Mad 63:1010-1014. 28. Philip P, Drivsho]m A, Hanson NE, Jansen MK, Kiliman SA (1980): Chromosomes and survival in multiple myeloma: A banding study of 25 cases. Cancer Genet Cytogenet 2:243257. 29. Hossfeld DK, Schmidt CG (1978): Chromosome findings in effusions from patients with Hodgkin's disease. Int J Cancer 2!:147-15~. 30. Van den Berghe H, Vermaelen K, Mecucci C, Barbieri D, Tricot G (1985): The 5 q - anomaly. Cancer Gonet Cytogenet I 7:189-255. 31. L.eBeau MM, Pettenati M l, Lemons RS, Diaz MO, Westbrook CA, Larson RA, Sherr CJ, Rowley ID (1986): Assignment of the GM-CSF, CSF-I. and FMS genes to human chromosome 5 provides evidence for linkage of a family of genes regulating hematopoic,,sis and for their involvement in the deletion (5q) in myc%id disorders. Cold Spring Harbor Symposia on Quantitative Biology 51:899-909. 32. Sherr CJ, Rettenmier CW, Sacca T~,,Roussel MF, Look AT, Stanley ER (1985): The c-fms proto-oncogene product is related to the receptor for the mononuclear phagocyte growth factor, CSF-1. Cell 41:665-~69. 33. Human Gone Mapt~ing 8 (1985): Eighth International Workshop on Human Gene Mapping, Helsinki. Cytogenet Cell Go'net 40:1-535.
ABSTRACT: Serial cytogenetic analyses from the bone marrow of a patient with blastic phase of a
Philadelphia chromosome-negative chronic myeloid leukemia revealed a t(3;5)(p21 ;q31). The literature on translocations involving chromosome 3 and the long arm of chromosome 5 is reviewed. The importance of breakpoints in band 5q31 is discussed.
INTRODUCTION
Chromosome abnormalities in nonlymphocytic leukemia have been much studied. Correlations between some chromosome abnormalities and the morphology of blast cells and/or the clinical course of the disease were found by several groups [1, 2]. Translocations involving chromosome 3 and the long arm of chromosome 5 have been reported in several cases of acute nonlymphocytic leukemia (ANLL) and myelodysplastic syndromes (MDS) [3-20]. We report here a further case in which a t(3;5)(p21;q31) arose in the setting of blastic phase of a Philadelphia (Ph) chromosome-negative chronic myeloid leukemia (CML).
CASE REPORT
The patient, a 17-year-old man, was first seen for Ph-negative CML in transition. At that time he was treated with hydroxyurea, which brought his white blood cell count (WBC) from 115 x 109/L down to 12 x 109/L. A week later, the WBC was at 18.5 x 109/L with 48% blasts, 2% metamyelocytes, 22% polymorphnnucleocytes, and 28% granulocytes. A diagnosis of blastic phase was made and chemotherapy i n c l u d i n g d a u n o m y c i n and cytosine arabinoside was started. A complete remission was achieved 3 weeks later and maintenance therapy was begun. Relapse occurred 23 months later. The WBC was at 1.4 x 10~/L with 13% blasts, hemoglobin was 9.8 g/dl, and platelets were 16 x 109/L. The bone marrow aspirate showed 33°/,, undifferentiated blasts. Complete remission was achieved 1 week later. The patient experienced a second relapse 8 months later. The bone marrow aspirate showed 30% myeloid blasts with maturation (FAB type m2). The WBC was 0.9 x 109/L with 14% blasts, and platelets were 23 x 109/L. The clinical course was then complicated by recurrent From SOREP, Departmentof Human Sciences, Universityof QuelM;cat Chicoutimi.Chicoutinli(M. D.) and the Departmentof Pediatric Pathology, MontrealChildren's I[ospital.Montreal (M. V.). Quebec.Canada. Address reprint requests to: Dr. M. De lIraekeleer. SOREP, Universityof Quebec at Chicautimi. 555 Boulevard de l'Universite, Chicoutimi. Quebec G711 2B1, Canada. Received April 29, 1988: accepted September 23, 1988.
163 © 1989 Elsevier SciencePublishingCo., Inc.
Cancer Genet Cytogenet37:163-168 (1989]
655 Avenueof the Americas,New York, NY 10010
0165-4608/89/S03.50
164
M. De Braekeleer and M. Vekemans infections and thrombocytopenia requiring frequent platelet transfusions. The patient is still in blastic phase. His last WBC was 59.4 x 109/L with 44% blasts, hemoglobin was 9.5 g/dl, and platelets were 19 x 109/L.
CYTOGENETIC STUDIES Serial cytogenetic analyses were performed on bone marrow cells immediately after collection and/or after 24- and 48-hour cultures with or without methotrexate and on peripheral blood cell cultures for 24 hours without phytohemagglutinin. G banding was performed by the trypsin-Giemsa method (GTG), and the karyotypes were arranged according to the recommendations of the [SCN [21]. An initial cytogenetic analysis of blood cells performed on April 9, 1984, showed a normal mate karyotype (18 cells). The analysis performed on April 30, 1984, when the patient was in blastic phase, showed the presence of a t(3;5)(p21;q31) in the 20 bone marrow cells examined (Fig. 1). The analysis was repeated when the patient -was in complete remission, and a normal karyotype was found at that time. No analysis was done at first relapse. At second relapse, the karyotype again showed the t(3;5)(p21;q31) without any additional abnormalities.
Figure I
G-bandedkaryotype showing the t(3;5)(p21;q31).
165
t(3;5) in Ph-Negative CML Table 1
Patients w i t h a t(3;5)-associated n o n l y m p h o c y t i c l e u k e m i a or myelodysplastic syndrome
Reference
Type of leukemia
Sex/age
[3]
M/45
Ph+CML in BP
[41
F/65
AML
[5] [61 [7]
[81 [9] [10]
F/23 F/47 F M M F/20 M/55 M/71
M2 foil MDS M6 M2 M2 M2 M4 M6 RAEB
Ill]
M/60
M4
[12] [13] [14]
M/32 M/21 F/65
M4 M4 M6
[15] [16] [17] [18] [19]
M/38 M/40 F/36 F/32 M/17
RA-M2 M4 M2 M2 Ph+CML Ph~-CML in BP
[201 Present study
F/7 M/16 M/17
M2 M5b Ph-CML in BP
Karyotype 46,XY,t(4;22)(q35;q11),t(3;5)(q27;q22), i( 17q)/50,XY,t(4; 22) ,t(3;5), + 8, + 15, + 21, + Ph ,i (17q)/50,XY,t[4:22),t(3 ;5), + 15, + 21, + Ph,i(17q), + mar 47,X,Xq-,-3,* t(3;5),- 5,- 5,- 11,+t(11;?), - 12,+t(12;17),- 17,- 18,-21,+ 6mar 46,XX,t(3;5)(q21;q31) 46,XX,t(3;5)(q21;q31) 46,XX,t(3;5)(q25;q31) 46,XY,t(3;5)(q24;q34) 46,XY,t(3;5)(q21;q31) 46,XX,t(3;5)(q26;q31) 46,XY,t(3;5)(q13;q23) 48,XY,+ 8, + ~1~,t(3;5)(pl 3:q13)/48,XY,+ 8, t(3;5),t(6;l 3)(p25;qi 1 ),+ ?del(5)(q31q35) 42,XY,t(3;5)(qter;q13),t(7;12)(q12;q14), l(7;10)(q12;q21),- 8,- 17,- 18,- 20 46,XY,t(3;5)(q25;q33) 46,XY,t(3;5)(q25;q31or32) 47,XX,t(3;5)(q21;q31),- 1,- 13,+ 8,+22, + der(1)t(1;13)(p36:ql 4) 46,XY,t(3;5)(q21;q31) 46,XY,t(3;5)(q21;q31) 46,XX,t(3;5)(q21;q31) 46,XX,t[3;5)(q21;q31) 46,XY,t(9;22)(q34;q11)/47,XY,t(9;22), + Ph/46,XY,t(9;22),t(3p;5q),t(6p;13q) 46,XY,t(9;22 )/46,XY,t(9;22), + Ph,-9/ 46,XY,t(9;22),t(3p;5q),t(6p;13q) 46,XX,t(3;5)(q24;q32) 46,XY,t(3;5)(q24;q32) 46,XY,t(3;5)(p21;q31)
DISCUSSION With the d e v e l o p m e n t of criteria for MDS a n d myeloproliferative disorders, it has b e c o m e clear that Ph-negative CML represents a heterogeneous group of diseases [22, 23]. S t u d i e s have also s h o w n a subset of patients with Ph-negative CML w i t h a r e a r r a n g e m e n t of c-abl a n d bcr, as typically seen in Ph-positive CML [24-26]. W h e t h e r the p a t i e n t reported here belongs to that subset is not k n o w n as no DNA a n a l y s i s was done. It is, however, n o t i c e a b l e that the patient achieved two c o m p l e t e r e m i s s i o n s , o n e lasting 23 m o n t h s a n d the other 8 m o n t h s . T w e n t y - t w o patients with a n o n l y m p h o c y t i c l e u k e m i a associated with a t(3;5) have n o w b e e n reported [3-20] (Table 1). A t(3;5) i n v o l v i n g the long arm of c h r o m o some 5 was also reported in a case of h y p e r e o s i n o p h i l i a s y n d r o m e [27], a case of m y e l o m a [28], a n d a case of H o d g k i n ' s disease [29]. Therefore, it appears that translocations i n v o l v i n g c h r o m o s o m e 3 a n d the long arm of c h r o m o s o m e 5 are specific to n o n l y m p h o c y t i c l e u k e m i a a n d MDS, as are deletions of 5q [30]. A l t h o u g h the t(3;5) was recognized as a n e w cytogenetic entity at the F o u r t h I n t e r n a t i o n a l W o r k s h o p o n
166
M. De Braekeleer and M. Vekemans
3
5
I
1
1:
®
• 2
00
0
0000 0000 000 000 0 0
0 0
000000
|**°°
0
Figure 2 Breakpoint distribution in t(3:5) in nonlymohocytic leukemia and myelodyspiastic disorders.
Chromosomes in Leukemia in 1982 [5], this abnormality had already been reported by Golomb et al. and Oshimura et al. in ]976 [!2, 74]. The sex ratio is not distorted, being ] 3 males and 9 females. The age at onset varies from 7 to 71 years. Originally, it was thought that the t(3:5) could be specifically associated with ANLL-M2 when it was recognized as a distinct entity 15, 7, 18]. However, the distribution of the types of leukemia shows that the translocation can be found in all types of n e n l y m p h o c y t i c leukemia, as it has been reported in eight cases 9f M2, five cases of M4. one case of M5, and three cases of M~5. The abnormality has also been found in MDS [10, 15] and in Ph-positive or -negatiw,~ CMI, in chronic and blastic phases [3, 19: present case[. Because the clinical and laboratory data are still sparse, it is impossible to see whether the t{3;5) is associated with a specific clinical picture or if it carries a poor or a good prognosis. Figure 2 shows the breakpoint distribution on chromosome 3 and on the long arm of c h r o m o s o m e 5. The breakpoints on chromosome 3 are distributed in nine bands, with eight breaks being in band 3q21. Twelve of the 20 breakpoints occurring in the long arm of chromosome 5 were assigned to band 5q32. Therefore, although eight of the 20 translocations with identified breakpoints were reported as t(3;5)(q21;q31), the specific rearrangement appears to be a break in band 5q3]. The distal part of the long arm of chromosome 5 contains a family of genes regulating hemopoiesis [31]. The granulocyte-macrophage colony stimulating factor (GM-CSF} gene was localized at bands 5q23-q31, the macrophage colony stimulating factor (CSF-1) at band 5q33.1, and the protooncogene FMS at bands 5q33.2-33.3 [31]. It was also s h o w n that the protooncogene FMS encodes a protein that is related or possibly identical to the receptor for CFS-1 [321. Moreover, the gone encoding the c~adrenergic surface receptor was m a p p e d to band 5q35 [331, and the gene encoding the platelet-derived growth factor receptor to bands 5q31-q32 (Y. Yarden, quoted in [31]~:. Therefore, there is evidence that a functional family of genes that regulate the growth of hematopoietic cells maps to a restricted region of 5q. it also raises the possibility that genes encoding other growth factors and receptors may be located in
t(3;5) i n P h - N e g a t i v e CML
167
t h e s a m e region. W h e t h e r t h e b r e a k in 5q31, as r e c o r d e d in t h e t(3;5), i n d u c e s a c t i v a t i o n or i n a c t i v a t i o n of a g r o w t h factor or a g r o w t h factor r e c e p t o r r e m a i n s to b e determined.
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