Tetraploid clone characterized by two t(15;17) in five cases of acute promyelocytic leukemia

Cancer Genetics and Cytogenetics 188 (2009) 57e59

Letter to the editor

Tetraploid clone characterized by two t(15;17) in five cases of acute promyelocytic leukemia More than 100 cases of acute myelocytic leukemia (AML) with tetraploidy or near-tetraploidy (NT) have been described in the literature to date [1,2]. These can be divided into primary and secondary NT-AML [3,4]. Primary NT-AML, usually seen in older patients with poor prognosis has chromosomal structural or numerical abnormalities, especially involving chromosomes 5 and 7 [2]. Secondary NT-AML is frequently seen in younger patients than the primary form and has specific chromosomal rearrangements, with a relatively good prognosis in most of them [4]. Among the latter, NT-AML with duplication of t(8;21) is the most common, with 13 cases reported, compared with only 6 cases of NT acute promyelocytic leukemia (APL) with double t(15;17) [5e11]. Here, we report five new cases of NT-APL with double t(15;17) abnormalities and discuss their possible clinical and biological features. From 1998 July to 2008 April, 660 APL patients were examined cytogenetically in our hospital. The NT type with double t(15;17) was detected in 5 of the 660 patients (0.75%). All were men, with a median age of 38 years (range, 21e68). Giant and bizarre blasts were seen on bone marrow smears in all five cases. Chromosome analysis with R-banding of bone marrow cells revealed the karyotype of the abnormal clone to be 92,XXYY,t(15;17)(q22;q21)2. Fusion of the PML and RARA genes was detected in three cases: in one case by fluorescence in situ hybridization analysis (FISH) using the Vysis LSI PML/RARA dualcolor, dual-fusion probe (Abbott Molecular, Des Plaines, IL) (case 2) and in two cases by reverse transcriptasee polymerase chain reaction (cases 3 and 4). Immunologically, the blasts expressed CD33 in five cases and CD13 in four cases. In addition, CD2 expression was seen in case 2 and CD34 in case 3, respectively. Flow cytometric analysis displayed a tetraploid peak (DNA index Z 1.998) in case 2. All five patients responded well to all-trans retinoic acid (ATRA) alone or a combination of ATRA and arsenic trioxide (As2O3) and remained in complete remission at writing. Acute promyelocytic leukemia is characterized by the translocation t(15;17)(q22;q21), the PMLeRARA fusion gene and a good response to ATRA or As2O3 [12]. Most cases exhibit a diploid karyotype with a single t(15;17). 0165-4608/09/$ e see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.cancergencyto.2008.08.017

Cases of NT-APL with double t(15;17) are extremely rare. Since 1999, only six such cases have been reported. The five new cases reported here brings to 11 the number of reported NT-APL cases with double t(15;17). Their clinical and laboratory data are presented in Table 1. Based on these data, we identified six clinical and biological features. (1) All these cases were East Asian in origin: 5 Chinese, 5 Japanese, and 1 Korean. To date, no NT-APL case with double t(15;17) has been documented in Western countries. (2) A male preponderance is evident, with 10 males and 1 female. (3) All cases had giant and bizarre blasts. Increased cellular DNA content was confirmed by the results of flow cytometric analysis in cases 2 and 8. (4) In terms of immunophenotypic data (available in 9 of the 11 cases), CD33 was expressed in all 9 cases and CD13 in 8 cases; the leukemic cells coexpressed CD2 in 5 cases and CD34 in 3 cases. (5) Reverse transcriptaseepolymerase chain reaction analysis was done in six cases. PML/RARA fusion transcription was detected in all of them, presenting short form in five cases and long form in 1 case. (6) Two patients did not respond to ATRA (cases 6 and 7), one patient (case 8) experienced multiple complete remission and relapse, and the remaining eight responded well to ATRA or to ATRA and As2O3. Our experience suggests that the NT with double t(15;17) in APL does not appear to affect the response to treatment or prognosis. In summary, we consider that NTAPL with a double t(15;17) chromosomal abnormality may be taken as a distinct cytogenetic subgroup with unique clinical and biological features. To elucidate its entity, it is necessary to study more APL patients with the NT karyotype and double t(15;17).

Acknowledgments This work was supported by a grant (wkj2005-2-025) from the Ministry of Health of the People’s Republic of China. We thank the Molecular Lab for providing reverse transcriptaseepolymerase chain reaction results and Dr. Mingqing Zhu for providing flow cytometry results.

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Table 1 Clinical and laboratory data for 11 acute promyelocytic leukemia patients with near-tetraploidy and double t(15;17) translocation Giant and bizarre blasts?

1

21/M

Yes

2

26/M

Yes

3

68/M

Yes

4

40/M

5

Double PML/RARA fusion signals

Outcome (duration)

Immunophenotype

Karyotype

FISH, %

RT-PCR

Treatment

Reference

46,XY,t(15;17)[3]/j92,XXYY,t(15;17)2[6]/j46, XY[1]

ND

ND

As2O3

CR and alive (6 moþ)

Present study

92,XXYY,t(15;17)2[10]

99.5

ND

ATRAþ As2O3

92,XXYY,t(15;17)2[5]/j46,XY[5]

ND

S

ATRAþ As2O3

92,XXYY,t(15;17)2[10]

ND

L

ATRA

38/M

Yes

CD13 14%, CD33 38%

92,XXYY,t(15;17)2[18]/j46,XY[2]

ND

ND

ATRA

6

56/M

Yes

92,XXYY,t(15;17)2[20]

93

S

ATRA

7

50/F

Yes

CD2þ, CD13þ, CD33þ, CD34þ, CD56þ CD2þ, CD13þ, CD33þ

92,XXYY,t(15;17)2[20]

99.5

ND

ATRA þ DNR

8

50/M

Yes

CD2þ, CD13þ, CD33þ, CD34þ, HLA-DRþ

74.1

S

ATRA þ IDA

9

24/M

Yes

CD2þ, CD13þ, CD33þ

ND

S

ATRA

CR

Au et al., 1999 [6]

10 11b

53/M 56/M

Yes Yes

ND ND

45,XY,add(1)(p36),9,der(15)t(15;17),17, add(20)(q13),21,þmar1,þmar2[2]/46,idem, þmar3[6]/45,idem,del(11)(p11),add(13)(p11), þ18,þ21,mar1,mar2[2]/86,XX,Y,Y, add(6)(p21)2,8,9,11,12,der(15) t(15;17)2,16,17,17,þ18,19,þmar4, þmar5[2]/46,XY[5] 73w89,XXY,Y[3],3[10],5[9],7[4], 9[7],11[9],14[10],15[9],t(15;17)[10], t(15;17)[4],der(15)t(15;17)[4],17[8],18[7], 19[9],20[3],þmar1[9],þmar22[10], þmar3[7][cp10]/46,XY[6] 92,XXYY,del(2),t(15;17)2[4]/46,XY[16] 90w92

CR and alive (2.5 moþ) CR and alive (12 moþ) CR and alive (48 moþ) CR and alive (120 moþ) NR; died on day 5a NR; died 10 d after admission Multiple CR and relapse

Present study

Yes

CD2 19.8%, CD13 78.4%, CD15 47%, CD33 91.1%, CD117 65.1% CD2 39.9%, CD13 45.1%, CD33 98.8%, MPO 32.9% CD13 88.8%, CD15 14.3%, CD33 90.2%, CD34 16.8% CD13 99.4%, CD33 99.9%

33.5 100

S ND

ATRA ATRA

CR CR

Kojima et al., 2003 [7] Kuyama et al., 2004 [10]

Present study Present study Present study Kaito et al., 2005 [11] Oh et al., 2003 [8]

Morita et al., 2004 [9]

Abbreviations: ATRA, all-trans retinoic acid; CR, complete remission; DNR, daunorubicin; F, female; IDA, idarubicin; L, long form; M, male; ND, not done; NR, no response; RT-PCR, reverse transcriptaseepolymerase chain reaction; S, short form. a Pulmonary embolism. b The metaphase cells could not be fully evaluated because of poor morphology of the chromosomes.

Letter to the editor / Cancer Genetics and Cytogenetics 188 (2009) 57e59

Case

Age, yr/jsex

Letter to the editor / Cancer Genetics and Cytogenetics 188 (2009) 57e59

Jinlan Pan Yongquan Xue* Huiying Qiu Yafang Wu Yong Wang Jun Zhang Juan Shen Key Laboratory of Thrombosis and Hemostasis Jiansu Institute of Hematology *The First Affiliated Hospital of Soochow University, Ministry of Health, 188 Shizi Street, Suzhou, 215006, China E-mail address: [email protected] (Y. Xue)

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