Cancer Genetics and Cytogenetics 158 (2005) 184–187

Short communication

Chromosome 7 abnormalities in acute megakaryoblasticleukemia associated with Down syndrome

Ken-ichiro Kobayashia,*, Ikuya Usamia, Masaru Kubotaa, Toshikazu Nishioa, Naoki Kakazub

aDepartment of Pediatrics, Kobe City General Hospital, 4-6 Minatojima-Nakamachi, Chuo-ku, Kobe 6500046, JapanbDepartment of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan

Received 7 May 2004; received in revised form 27 August 2004; accepted 31 August 2004

Abstract A 2-year-old girl with Down syndrome (DS) developed acute megakaryoblastic leukemia (AMKL)following a transient myeloproliferative disorder (TMD). The blast cells showed an altered karyotypeof 47,XX,r(7),�21c. Serial cytogenetic studies during the course of the illness showed rapidstepwise clonal chromosome changes, including a ring chromosome 7, associated with treatmentrefractoriness. We reviewed 10 published cases of Down syndrome-related AMKL (DS-AMKL)showing chromosome 7 abnormalities and found that these changes do not carry the same prognosticweight as for non-DS children. For DS-AMKL, therefore, other prognostic factors besides clonalcytogenetic changes need to be identified for planning optimal therapy. � 2005 Elsevier Inc.All rights reserved.

1. Introduction

The predisposition of children with Down syndrome (DS)to leukemia is well established. These children are prone todevelop acute megakaryoblastic leukemia (AMKL) whenthey are younger than 3 years [1–3]. Their characteristicclinical picture is attributed to the gene dosage effect ofconstitutional 21 trisomy [4,5]. The acquired mutations inthe hematopoietic transcription factor gene GATA1 were re-cently found to be responsible for the first genetic hit inthe characteristic hematological change, but the second hitfor the full expression of AMKL is still a matter of discussion[6,7]. Despite an increasing recognition of the importanceof cytogenetic changes in the classification and treatment ofacute myeloid leukemia, there is only limited information onthe disease-specific cytogenetic changes and their prognosticweight in DS-AMKL [8–10]. We describe the case of a2-year-old girl with DS-AMKL associated with ring chromo-some 7 and review the clinical implications of chromosome7 abnormalities on DS-AMKL.

* Corresponding author. Tel. �81-78-302-4321; fax: �81-78-302-7537.

E-mail address: ckg-kobayashi@rio.odn.ne.jp (K. Kobayashi).

0165-4608/05/$ – see front matter � 2005 Elsevier Inc. All rights reserved.doi:10.1016/j.cancergencyto.2004.08.036

2. Patient report

A girl infant was born at full term with an Apgar scoreof 8 at 1 minute to a healthy 30-year-old mother. The babyweighed 4,396 g and had the characteristic facial dysmorph-ism of Down syndrome; she was found to have hyperleuko-cytosis of 34 × 109/L with 36% blasts. Cytogenetic analysisof the peripheral blood showed trisomy 21, with no otherchromosome abnormalities. The diagnosis of a transient my-eloproliferative disorder (TMD) was made; the blood filmhad normalized within 2 months.

At the age of 16 months, the patient presented with pallorand hepatomegaly 3 cm below the right costal margin. Acomplete blood count disclosed hemoglobin of 6.8 g/dL,a platelet count of 82 × 109/L , and a leukocyte count of6.0 × 109/L with 7% of blast cells. The blasts had a highnuclear–cytoplasmic ratio, with fine nuclear chromatin andprominent nucleoli showing cytoplasmic budding. Series ofstains were negative for peroxidase, periodic acid-Schiff,and electron platelet peroxidase. Immunophenotype ofblasts showed CD7�, CD33�, CD 34�, CD 41a�, CD 61�,and glycophorin-A�. A bone marrow aspirate showed 6%of blast cells with dysplastic hematopoiesis, includinghypogranular granulocytes, megaloblastic erythroid precur-sors, and micromegakaryocytes. Cytogenetic analysis ofbone marrow cells cultured without a mitogen disclosed47,XX,r(7),�21c in 2 of the 20 cells analyzed. Based on

K. Kobayashi et al. / Cancer Genetics and Cytogenetics 158 (2005) 184–187 185

these findings, the diagnosis of a myelodysplastic syndrome(MDS) was established. Although chemotherapy was con-sidered, the pancytopenia resolved spontaneously within 2months, coinciding with the disappearance of the circulatingblast cells.

At the age of 24 months, blast cells reemerged in connec-tion with the progression of the thrombocytopenia andanemia, resulting in a leukocyte count of 8.1 × 109/L with31% blasts. Cytologic and cytogenetic findings showed thatthe blast cells were identical to those seen in MDS. A tre-phine biopsy revealed the presence of atypical megakaryo-cyte proliferation and prominent fibrosis. The final diagnosisof AMKL led to the initiation of combination therapy ofpirarubicin hydrochloride (25 mg/m2 per day for 2 days),cytosine arabinoside (100 mg/m2 per day for 7 days), andetoposide (150 mg/m2 per day for 3 days) [11]. Completeremission was achieved after two courses of the therapy.The continuation of the consolidation therapy was unevent-ful and without marked side effects, but the patient eventuallyrelapsed 6 months after the initiation of the therapy. Duringthe latter course of the disease, serial cytogenetic studiesusing a standard G-banding method showed stepwise clonalchanges (Table 1). In the terminal phase, cytogenetic analysisof peripheral blood leukemic cells showed complex chromo-somal abnormalities, including two additional materials ofunknown origin (add) and one clonal marker chromosome(mar) that could not be characterized with G-banding. Spec-tral karyotyping (SKY) analysis was therefore performedas described previously [12]. SKY identified add(17)(p11),add(7)(q22), and a marker chromosome to be der(17)(qter→q2?1::p11→qter), der(7)t(7;11)(q36;p13)?inv(7)(q21q22),and der(7)del(7)(p11)t(7;14)(q36;q11), respectively (Fig. 1).Additional high-dose cytosine arabinoside and idarubicinshowed limited effect, and the patient finally died at 38months of age.

3. Discussion

Not only is the incidence of leukemia approximately 20times higher in children with DS than in non-DS children,

Table 1Serial cytogenetic changes during the clinical course of the patient

Age (mo) Stage of disease Chromosome findings

0 TMD 47,XX,�21c[20]16 MDS 47,XX,�21c[18]/47,idem,r(7)[2]24 AMKL (onset) 47,XX,�21c[2]/47,idem,r(7)[7]26 AMKL (remission) 47,XX,�21c[20]30 AMKL (relapse) 47,XX,�21c[1]/44,idem,�4,r(7),�12,

add(12)(q24),�17,�18,�mar[1]33 AMKL (terminal) 47,XX,r(7),add(17)(p11),�21c[5]/

46,XX,der(4;11)(q10;q10),add(7)(q22),add(17)(p11),�21c[11]/46,XX,�7,�14,add(17)(p11),�21c,�mar[4]

Abbreviations: AMKL, acute megakaryoblastic leukemia; MDS, myelo-dysplastic syndrome; TMD, transient myeloproliferative disorder.

but there is also a marked increase in AMKL. The lattertypically develops at less than 3 years of age, following aprephasic MDS along with additional complex chromosomechanges besides the constitutional 21 trisomy [1–3]. In addi-tion to the characteristic disease progression form, DS-AMKL patients show a significantly higher event-freesurvival (EFS) rate than non-DS AML patients treated witha cytosine arabinoside-based protocol; Kojima et al. [11]reported an 8-year EFS rate of 80 � 7% and Ravindranathet al. [13] a 4-year rate of 100%. The clinical pictures, includ-ing higher sensitivity to chemotherapy, may be related tothe additional 21 chromosome, but the precise mechanismsare still a matter of discussion [4,5].

Our patient showed unusual treatment refractoriness inthe absence of known poor prognostic factors or treatment-related toxicity [14]. Stepwise chromosome changes werefound, including a ring chromosome 7, associated with pro-gression of the disease. Generally, a complex karyotype andthe presence of a ring chromosome are correlated with a poorprognosis in MDS and acute nonlymphoblastic leukemia[15,16]. Chromosome 7 abnormalities, including monosomy7, are also seen in a wide array of pediatric genetic myelo-poietic disorders, such as pediatric MDS, congenital neu-tropenia, Shwachman–Diamond syndrome, and Fanconianemia [17]. Although knowledge of clonal chromosomechanges in hematological disorders is increasing, the prog-nostic implications of such changes on DS-AMKL haverarely been evaluated. We therefore reviewed 11 patients(ours included) with DS-AMKL associated with chromo-some 7 abnormalities (Table 2) [10,11,18,19].

The patients’ initial response to therapy was excellent,with a remission induction rate of 100%. Because the patientswere individually treated (without stem cell transplantation),their final treatment outcomes have not been fully assessed.Of the four who are listed (patients 4–7), two eventuallyrelapsed, but the remaining two remained in long-term remis-sion. Overall, at least 5 of the 11 patients showed favorableoutcomes with the aid of conventional chemotherapy alone.

Our review suggests that chromosome changes in DS-AMKL patients do not carry the same prognostic weight asfor non-DS patients. In particular, the unstimulated lympho-cytes from DS are more sensitive to the induction of dicentricand ring aberrations caused by x-rays than are normal karyo-types [20–23]. In taking account of the biologic nature of DS,the complex chromosome changes, including chromosome7 abnormalities in DS-AMKL, may reflect their inherentcytogenetic instability, acquired genotoxic damage, or both.The review provided further support for our notion that thechromosome 7 abnormalities seen in DS-AMKL carry lessprognostic significance than they do in non-DS patients.

DS-AMKL is believed to be a relatively homogeneoussubgroup of leukemias, with characteristic clinical presenta-tions and excellent response rate to chemotherapy on thebasis of 21 trisomy [1–3]. Recently reported mutations inGATA1 provide helpful clues regarding the leukemogenesisof DS-AMKL [6,7], but several clinical diversities remain

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Fig. 1. SKY analysis for three cells (A, B, and C) from the present case in the terminal phase. The G-banded karyotypes of these cells were:(A) 47,XX,r(7),add(17)(p11),�21c; (B) 46,XX,der(4;11)(q10;q10),add(7)(q22),add(17)(p11),�21c;(C)45,XX,�7,�14,add(17)(p11),�21c,�22,�mar (the totalloss of chromosome 22 was a random loss). For each cell, from left to right: inverted DAPI images, red–green–blue (RGB) display color images, spectra-based classified color images, and the karyotype table using the classified color images. Arrows indicate abnormal chromosomes. Numbers next to theclassified color images in the karyotype table indicate the origin of the chromosomal material in abnormal chromosomes.

underestimated, such as differences in surface phenotypesand clonal cytogenetic changes [11,24]. Even in view of

generally favorable outcomes [11,13], a subgroup with poorprognosis, as exemplified by our patient, shows the need

Table 2Reported cases of acute megakaryoblastic leukemia with Down syndrome associated with chromosome 7 abnormalities

Initial responsePatient no. Age (mo) Karyotype to chemotherapy Survival perioda References

1 21 47,XX,del(6)(q23q25),�7,�21c,�r(?7) CR 8 mo Hayashi et al., 1988 [10]2 10 47,XY,der(7)t(2;7)(q13;p15),der(12)t(6;12) CR 5 mo Hayashi et al., 1988 [10]

(p11;p11),�21c3 24 47,XX,del(7)(q32),�21c CR 3 mo� Hayashi et al., 1988 [10]4 18 47,XY,der(3)t(3;3)(p25;p10),i(7q),der(17) CR ND Kojima et al., 2000 [11]

t(1;17)(q25;q25),�21c5 16 48,XY,�7,�21c,�r,�mar CR ND Kojima et al., 2000 [11]6 28 48,XX,�7,�8,�21c,�mar CR ND Kojima et al., 2000 [11]7 46 47,XY,�6,�7,�8,�10,�18,�21c,�r CR ND Kojima et al., 2000 [11]8 38 47,XY,�7,del(16q),�21c,�r CR Accidental death Bunin et al., 1991 [18]9 34 47,XY,�7,�21c,�mar CR 30 mo� Bunin et al., 1991 [18]

10 25 47,XX,del(7)(q32),�21c CR 30 mo� Miyajima et al., 1991 [19]11 25 47,XX,r(7),�21c CR 14 mo Present case

Abbreviations: CR, complete remission; ND, not described.a A plus sign indicates that the patient was still alive.

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for investigation of the clinical heterogeneity of the diseaseitself. When treating DS-AMKL, higher regimen-relatedtoxicity and genotoxic damage are often the principal con-cerns [11,13,14]. To plan optimal therapy with less toxiceffect, additional prognostic indicators need to be identified,in addition to the cytogenetic abnormalities.

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