CD19-positive acute myeloblastic leukemia with trisomy 21 as a sole acquired karyotypic abnormality

CD19-positive acute myeloblastic leukemia with trisomy 21 as a sole acquired karyotypic abnormality 1 2 first-author 1 2 2 3 2 3 2 3 1 2 3 corresp ‡Corresponding Author ‡Corresponding Author †E-mail:jiej@hzcnc.com †E-mail:jiej@hzcnc.com jiej@hzcnc.com Department of Hematology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China Department of Hematology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China Institute of Hematology, Zhejiang University, Hangzhou 310003, China Institute of Hematology, Zhejiang University, Hangzhou 310003, China Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, China Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, China We report that a 63-year-old Chinese female had acute myeloblastic leukemia (AML) in which trisomy 21 (+21) was found as the sole acquired karyotypic abnormality. The blasts were positive for myeloperoxidase, and the immunophenotype was positive for cluster of differentiation 19 (CD19), CD33, CD34, and human leukocyte antigens (HLA)-DR. The chromosomal analysis of bone marrow showed 47,XX,+21[2]/46,XX[18]. Fluorescent in situ hybridization (FISH) showed that three copies of AML1 were situated in separate chromosomes, and that t(8;21) was negative. The patient did not have any features of Down syndrome. A diagnosis of CD19-positive AML-M5 was established with trisomy 21 as a sole acquired karyotypic abnormality. The patient did not respond well to chemotherapy and died three months after the diagnosis. This is the first reported case of CD19-positive AML with trisomy 21 as the sole cytogenetic abnormality. The possible prognostic significance of the finding in AML with +21 as the sole acquired karyotypic abnormality was discussed. Trisomy 21 Acute myeloid leukemia Cluster of differentiation 19 (CD19) INTRODUCTION 1 Trisomy 21 (+21) is one of the five most frequent numerical abnormalities occurring in human neoplasms (Heim and Mitelman, 1986 1986 ); however, in most cases, the extra chromosome 21 is present together with other numerical and/or structural changes. Acquired trisomy 21 is the single karyotypic abnormality in only 0.4% of human neoplasms, and the frequency was slightly lower in lymphoid than in myeloid malignancies (0.2% vs. 1.0%) (Mitelman et al., 1990 1990 ). The incidence of trisomy 21 as a sole abnormality was between 0.3% and 0.6 % in all patients with acute myeloblastic leukemia (AML). Morphologically, AML with trisomy 21 as a sole abnormality preferentially shows M2 or M4 phenotype according to the French-American-British (FAB) classification (Gallego et al., 1997 1997 ; Wan et al., 1999 1999 ). Patients with this aberration appear to have a poor prognosis (Wan et al., 1999 1999 ; Cortes et al., 1995 1995 ; Wei et al., 1996 1996 ), but the clinical and prognostic implications of this karyotypic abnormality in AML remain unclear. Recently, a small number of cases (Wei et al., 1996 1996 ; Kondo et al., 2001 2001 ; Yamamoto et al., 2002 2002 ; Udayakumar et al., 2007 2007 ) reported the relationship between AML with trisomy 21 as a sole acquired abnormality and expression of cluster of differentiation 7 (CD7), and reported that co-expression of CD7 is probably indicative of the very early stage at which the cell became malignant (Udayakumar et al., 2007 2007 ). Here, we presented a case of CD19-positive AML with trisomy 21 as a sole acquired karyotypic abnormality and discussed its possible prognostic significance. CASE PRESENTATION 1 A 63-year-old Chinese woman was admitted to our hospital because of debilitation and fever for 3 months in July 2005. Physical examination showed no hepatosplenomegaly or lymphadenopathy. Peripheral blood counts showed hemoglobin 59 g/L, platelets 205×10 9 L −1 , and leukocytes 4.1×10 9 L −1 with 13% blasts, 7% neutrophils, 12% monocytes, and 68% lymphocytes. Bone marrow aspirate showed a hypercellular marrow with 68.5% monoblasts. The blasts were positive for myeloperoxidase, sudan black, and non-specific esterase, and were sensitive to fluoride inhibition. Therefore, the patient was diagnosed as AML FAB M5 (Fig. 1 1 ). Immunophenotypic analysis by flow cytometry revealed that the blasts were positive for CD19 (38.56%), CD33 (20.05%), CD34 (75.29%), human leukocyte antigens (HLA)-DR (63.94%), but negative for other lymphoid markers including CD3, CD7, CD10, CD22, CD61, CD56, glycophorin A (GPA), CD79a, and cyCD3 (Fig. 2 2 , see Page 835). Conventional cytogenetics was performed at the time of diagnosis. Chromosomes were R-banded on unstimulated bone marrow cells after a 24-h culture. The cells were grown in RPMI 1640 (Sigma, Schnelldorf, Germany) supplemented with 20% (v/v) fetal bovine serum. At least 20 metaphases were analyzed. Karyotypes were described according to the International System for Human Cytogenetic Nomenclature criteria (Shaffer and Tommerup, 2005 2005 ). The remaining fixed cell pellets were stored at −20 °C for further fluorescent in situ hybridization (FISH) studies. Chromosome analysis of the bone marrow cells showed 47,XX,+21[2]/46,XX[18] (Fig. 3 3 ). FISH analysis was performed on interphase/metaphase cells from the patient’s bone marrow cells. Four hundred interphase/metaphase nuclei were counted for each hybridization assay. We used spectrum red- and spectrum green-conjugated dual-color break-apart probe specific for the AML1 gene (Cytocell, UK) to confirm the presence of extra chromosome 21, and found that three copies of AML1 were situated in separate chromosomes, which suggested chromosome 21 (Fig. 4 4 ). In addition, Vysis dual-color, dual-fusion, locus-specific identifiers (LSI) AML1/ETO probes (Abbott Molecular/Vysis, Des Plaines, IL, USA) were used according to the manufacturer’s recommendations. The LSI AML1 probe was labelled with spectrum green and the LSI ETO probe was labelled with spectrum orange. Three-green, two-orange signal pattern was detected, but AML1/ETO fusion signal was not detected. We considered trisomy 21 to be acquired when the patient showed no phenotypic characteristics of Down syndrome, such as developmental retardation, brachycephaly, epicanthal folds, and speckled iris. The patient was diagnosed with AML-M5 with +21 as the sole acquired karyotypic abnormality, and treated with cytosine arabinoside (100 mg/m 2 , continuous infusion, Days 1~7) and homoharringtonine (6 mg, Days 1~3). However, a repeated bone marrow showed a refractory state. The patient was then treated with cytosine arabinoside (100 mg/m 2 , continuous infusion, Days 1~7) and etoposide (100 mg, Days 1~7). Unfortunately, she died of refractory leukemia after the second treatment, with survival duration of three months. DISCUSSION 1 Trisomy 21 has been demonstrated to be a recurring cytogenetic abnormality in AML and myelodysplastic syndrome (MDS). Trisomy may contribute to leukemogenesis by a gene dosage effect; whereby the presence of an increased copy number of certain genes gives a cell survival advantage and hence neoplastic potential (Sacchi, 1992 1992 ). Cells trisomic for chromosome 21 could be over-proliferating due to the enhanced expression of a tumourigenic gene (Shen et al., 1995 1995 ). The incidence of trisomy 21 as a sole cytogenetic anomaly in the de novo AML varies from 0.3% to 0.6% and from 2% to 6.7%, when it is associated with other anomalies whose presence rather than trisomy 21 determines the clinical outcome (Mitelman, 1994 1994 ; Mitelman et al., 1990 1990 ; Cortes et al., 1995 1995 ; Wei et al., 1996 1996 ; Berger et al., 1987 1987 ). Dewald et al.( 1990 1990 ) reported that trisomy 21 was observed as a sole acquired abnormality in 13 patients who had hematologic malignancies, of whom 12 had myeloid, including 5 myelodysplastic syndromes, 3 AML-M4, 3 AML-M2, and 1 AML-M7, and the remaining one had lymphoid leukemia. Many AML cases with trisomy 21 as a sole anomaly had been reported. Most of them were associated with AML-M2 or AML-M4, and the remaining cases included AML-M1, AML-M3, AML-M5, AML-M6, and AML-M7 (Table 1 1 ) (Dewald et al., 1990 1990 ; Mitelman, 1994 1994 ; Cortes et al., 1995 1995 ; Gallego et al., 1997 1997 ; Wei et al., 1996 1996 ; Wan et al., 1999 1999 ; Kondo et al., 2001 2001 ; Yamamoto et al., 2002 2002 ; Udayakumar et al., 2007 2007 ). Trisomy 21 also had been documented in 16 patients with myelodysplastic syndromes, 6 chronic myelomonocytic leukemia, 2 acute lymphocytic leukemia (ALL), 2 bilineal leukemia, and 2 undifferentiated leukemia (Mitelman, 1994 1994 ). By comparison, the most common hematological malignancies in patients with constitutional trisomy 21 (Down syndrome) are ALL and AML-M7 (Wan et al., 1999 1999 ; Hasle et al., 2000 2000 ). Here, we reported a new case of AML-M5 with trisomy 21 as the sole acquired karyotypic abnormality, which is in accordance with the observation reported in most cases that trisomy 21 was present along with normal clones (Gallego et al., 1997 1997 ; Wan et al., 1999 1999 ; Wei et al., 1996 1996 ; Yamamoto et al., 2002 2002 ; Dewald et al., 1990 1990 ). When the patients were first diagnosed M: male; F; female; NA: not available; +: positive; −: negative; CR: complete remission; FAB: French-American-British; Os: overall survival; ABMT: autologous bone marrow transplant; MDS: myelodysplastic syndrome References Year Country Sex/age FAB subtype CD7 CD19 Outcome Os (month) * * Wei et al.( 1996 1996 ) 1996 China M/35 AML-M4 NA NA Died of refractory leukemia 9 Taiwan, China M/30 AML NA NA Died of internal bleeding 3 d after chemotherapy 0.1 Gallego et al.( 1997 1997 ) 1997 Spain M/86 AML-M5b NA NA No treatment NA Wan et al.( 1999 1999 ) 1999 China M/28 AML-M2 NA NA CR, received an ABMT 24 F/78 AML-M4 NA NA No treatment NA Kondo et al.( 2001 2001 ) 2001 Japan M/21 AML-M2 + − CR well at 4 months NA Yamamoto et al.( 2002 2002 ) 2002 Japan M/49 AML-M2 + − CR, MDS 2 years later, leukemia 3 years later, died at 4 years 48 Udayakumar et al.( 2007 2007 ) 2007 Oman M/24 AML-M2 + − CR, but relapsed soon NA Present case 2008 China F/61 AML-M5b − + Did not received CR 3 In children, trisomy 21 as the sole chromosomal abnormality in ALL represents a good prognosis both in patients with Down syndrome and non-Down syndrome (Watson et al., 1993 1993 ; Raimondi et al., 1992 1992 ). AML in Down syndrome also showed high responsiveness to chemotherapy with a good event-free survival (Ravindranath et al., 1992 1992 ). In adults, the prognostic significance of trisomy 21 as the sole abnormality in AML remains unclear. A higher complete remission (CR) had previously been reported in AML with trisomy 21 (Arthur et al., 1989 1989 ), but a more recent study (Cortes et al., 1995 1995 ) showed that trisomy 21 in AML typically presented in conjunction with other cytogenetic changes, whose presence, rather than trisomy 21, determined the clinical outcome, and more studies (Wan et al., 1999 1999 ; Cortes et al., 1995 1995 ; Wei et al., 1996 1996 ; Dewald et al., 1990 1990 ) showed that AML patients with acquired trisomy 21 as sole abnormality had a poor prognosis. In our case, the patient also had poor prognosis, which is concordant with the poor prognosis reported in AML patients with trisomy 21 as the sole abnormality. Expression of lymphoid antigen is common in AML. CD7 is the most commonly expressed lymphoid antigen in AML (11%~29%) (Drexler et al., 1993 1993 ; Kita et al., 1993 1993 ), and CD2 is expressed in 16%~21% and CD19 in 7%~14% (Bradstock et al., 1994 1994 ; Ball et al., 1991 1991 ). Recently, Kondo et al.( 2001 2001 ), Yamamoto et al.( 2002 2002 ), and Udayakumar et al.( 2007 2007 ) reported the relation between AML with trisomy 21 as a sole acquired abnormality and expression of CD7, suggesting that co-expression of CD7 was probably indicative of the very early stage, at which the cell became malignant (Udayakumar et al., 2007 2007 ). The biological and clinical significance of CD7 expression in AML is not fully understood, although CD7-positive AML patients have a significantly lower response rate and poorer prognosis than CD7-negative AML patients (Drexler et al., 1993 1993 ). It has been reported that co-expression of CD7 in cases of AML with acquired trisomy 21 is 12%~17% in the overall group of AML patients (Kita et al., 1993 1993 ), and it is speculated that there are more cases of CD7-positive AML with acquired trisomy 21 (Kondo et al., 2001 2001 ; Udayakumar et al., 2007 2007 ). However, in our case, the patient did not express CD7, which was probably due to that most CD7-positive AML was associated with AML-M0, AML-M1, AML-M2, and AML-M4 (Saxena et al., 1998 1998 ). CD19 is a B-lymphocyte marker, whose expression is associated with pediatric AML-M2 and the t(8;21) translocation (Schwarzinger et al., 1990 1990 ). The biological and clinical significance of CD19 expression in AML is not clear, although it was reported that CD19-positive AML patients had a short survival (Solary et al., 1992 1992 ). In our case, the CD19-positive AML patient, without t(8;21) translocation, had a poor prognosis, a 3-month survival, which is much shorter than the average survival duration of 12.5 months in our department for AML with trisomy 21 as a sole acquired abnormality, which did not express lymphocytic marker. We, therefore, speculate that the AML patients with trisomy 21 as a sole acquired abnormality who expressed lymphocytic markers probably have a poor prognosis. However, the role of lymphoid antigen expression in response to treatment in AML patients with trisomy 21 needs to be further studied. CONCLUSION 1 In this case, AML was found to have trisomy 21 as the sole acquired karyotypic abnormality. The patient did not respond well to chemotherapy and died three months after the diagnosis. More cases of AML with sole acquired trisomy 21 need to be immunophenotypically analyzed to assess the prognostic significance of lymphoid antigen expression. 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