Koncor1_2014.PM6 39 R A D IA T IO N M E D IC IN E A N D O N C O L O G Y IJMMR 2015 Vol. 1 No. 1 PROGNOSTIC SIGNIFICANCE OF CD56 EXPRESSION IN ACUTE LEUKEMIAS B. M. Ahmed1, N. A. Kantoush2, M. A. Ismail1, D. A. Abd-El Haleem2 1AIN SHAMS UNIVERSITY, CAIRO, EGYPT 2NATIONAL RESEARCH CENTER, CAIRO, EGYPT Background. CD56 expression was extensively investigated in cases of acute leukemia. Many studies associated it with short overall survival, unfavorable outcome, lower rates or short complete remission, however the results remain controversial. Objectives. The aim of this study was to investigate the frequency and prognostic relevance of CD56 expression in patients with acute leukemia and to compare its value with other standard prognostic factors, such as age, gender, leukocytosis, morphologic subtypes, extramedullary invasion, cytogenetic abnormalities and performance status. Methods. Forty cases of acute leukemia treated at Ain Shmas University hospitals were investigated. They were classified by the French-American-British group (FAB) criteria, flow cytometry, and cytogenetics data. They included twenty cases of acute myeloid leukemia (AML) and twenty cases of acute lymphoblastic leukemia (ALL). Results. CD56 positive expression was detected in nine cases of AML (45 %), and only in two patients with ALL (10 %). The highest incidence of CD56 positivity was in FAB subtypes M1 (35 %) and M2 (35 %).Association studies between CD56 expression and other prognostic factors in AML cases showed no significant association with age, gender, clinical presentation, hematological data or cytogenetic risk groups. Incidence of relapse was higher in AML patients expressing CD56 than those who did not (66.7 % vs 10 %, P=0.01). Higher death rates were encountered in AML cases with CD56 expression than those without (55.6 % vs 10 %, P=0.032). Conclusions. CD56 antigenic expression in AML cases represents an adverse prognostic factor. It should be regularly investigated in cases of AML for better prognostic stratification and assessment. KEY WORDS: CD56; leukemia, myeloid; prognosis Introduction Acute leukemia is a heterogeneous group of disorders. They have various morphological, immu- nophenotypic and cytogenetic patterns. Identifying these characteristics is useful for prediction of the- rapy responses and prognosis of the disease [1]. Several phenotypic markers demonstrated to have clinical significance including detection of minimal residual disease [2, 3] rate and duration of complete remission (CR), disease-free survival, and overall survival (OS) [3]. CD56, a neural cell adhesion molecule (NCAM), is an early described natural killer cell-associated antigen. It mediates cell-to-cell interaction and is possibly involved in cell-mediated cytotoxicity. This antigen is also found in a subset of CD3+ cytotoxic T-cells and a small population of CD4+ T-cells and monocytes [4]. It is expressed in various hemato- poietic neoplasms, including acute myeloid leuke- mia(AML) [5], acute lymphoblastic leukemia (ALL) [6], lymphoma [7], and myeloma cells [8]. Being a cell adhesion molecule, CD56 expression on tumor cells is believed to play a role in their localization with involvement of extramedullary metastasis [9]. The prognostic value of CD56 expression in cases of acute leukemia has been extensively investigated but with few consistent results [3]. Some investigators associated CD56 expression with short OS [5, 10–12], and lower CR rates [10] in AML patient. Although Ferrara et al.[12] reported short OS in AML cases expressing CD56; they could not detect association of this marker with the rate of CR in M3 AML cases. Moreover, Chang et al. studied 379 cases of AML including all subtypes except M3 and reported that the CR rate was not associated with CD56 expression, but with CD34 and HLA-DR expression [13]. The aim of this study is to evaluate the prognostic role of CD56 expression in newly diagnosed acute Address for correspondence: Mona Ahmed Ismail, Department of Clinical and Chemical Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt B. M. Ahmed et al. International Journal of Medicine and Medical Research 2015, Volume 1, Number 1, p. 39-44 copyright © 2015, TSMU, All Rights Reserved 40 R A D IA T IO N M E D IC IN E A N D O N C O L O G Y IJMMR 2015 Vol. 1 No. 1 leukemia including AML and ALL cases and correlate the results with other prognostic factors. Methods Patients This study was carried out on 40 newly diagno- sed cases of acute leukemia. It included 20 AML and 20 ALL patients presented at the Hematology/ Oncology Clinics in the Internal Medicine and Pe- diatric Hospitals, Ain Shams University, Cairo, Egypt. Diagnosis and classification of acute leukemia was based on WHO (2008) [14] and FAB [15] criteria. Bone marrow and peripheral blood samples obtained at presentation were examined for morphology, immunophenotyping and complementary cytoge- netics. Another bone marrow samples were taken on the 28th day to evaluate response to induction therapy. Response to treatment was considered ineffective if more than 5 % blasts were detected in BM on the 28th day. Immunophenotyping Flow-cytometric analyses were performed as previously described [16]. The reactivity for the following markers was analyzed: a panel of fluorescein isothiocyanate (FITC)/phycoerythrin (PE) conjugated monoclonal antibodies to B-lineage markers (CD19, CD10, CD20, CD79a), T-lineage markers (CD2, CD3, CD5, CD7, cytCD3), myeloid markers (CD13, CD33, CD15, MPO, CD61, glycophorin, CD117), monocytic markers (CD14), and common progenitors markers (CD34, HLA-DR), supplied by Beckman Coulter, France. In addition, MoAb NCAM-PE (clone NCAM) (MiltenyiBiotec, Germany) for detection of CD56 was used. Cells were considered positive for a certain marker when �20 % of blasts expressed it, except for CD56, CD34 and intracellular MPO, where expression of �10 % of blasts was reported as positive. Cytogenetic analysis Leukemic cells were cultured, and the chro- mosomes were banded. Cytogenetic abnormalities were determined according to the International System for Human Cytogenetic Nomenclature [17]. Cytogenetic results were categorized into favorable, intermediate and unfavorable risk group. Statistical analysis Statistical analysis of the data was performed by using SPSS 15 software package and Windows 7® operating system. Categorical data parameters were presented in terms of frequency and percent age. Comparisons and associations that involve categorical variables were done by chi square test or Fisher exact test depending on the nature of the data. Continuous data parameters were described as middle, standard deviation (SD), median and interquartile range (IQR). Results Forty acute leukemia patients (20 AML and 20 ALL) were enrolled in this study. Table 1 summarizes age, gender, and clinical findings in the studied AML and ALL cases. According to FAB criteria, AML patients were classified into: 7 (35 %) M1, 7 (35 %) M2, 4 (20 %) M3, one (5 %) M4 and one (5 %) M5 case. ALL were classified into 17 (85 %) B-ALL and 3 (15 %) T-ALL cases. Successful mitosis was encountered in 18/20 (90 %) AML cases. Ten of these cases (55 %) were categorized as favorable [t(8:21), inv(16),t(15:17)], 6 (33.3 %) were intermediate (+8, normal) and 2 (11 %) cases were poor risk group [t(9:22), 11q23]. Successful mitosis was obtained in 12(60 %) of ALL cases. Three ALL cases (25 %) were classified as favorable risk (del 6q, hyperdiploidy>50), 5(41 %) were intermediate risk (normal), and 4(33 %) were poor risk group ( t(9:22), hypodyploidy<45). Our follow up of AML cases during induction period showed that 12 (63.2 %) AML cases showed good response to chemotherapy and achieved complete remission, while 7 patients (36.8 %) relap- sed, and one case was missed. Six of the relapsed patients died. Meanwhile, 14 (70 %) ALL patients showed good response to chemotherapy and achieved complete remission, while five cases (25 %) relapsed, 3 of them died. CD56 expression and association studies: Nine AML cases (45 %) were positive for CD56, while 11 (55 %) were negative. CD56 and CD34 coexpression was found in 2 cases (10 %). None of our AML cases co-expressed CD56 and CD7.Only 2 ALL cases (10 %) expressed CD56. One ALL case co-expressed CD56 and CD34.There was a statistically significant positive association between CD56 positive expression and CD117 in AML (p<0.05). No significant association was found between CD56 positive expression and immuno- Table 1. Demographic and clinical findings in AML and ALL cases � ���� ����� ����� ����� � ��� ���� � �� �� � � � � ����� ������ � ��� ������ � � ����������� �������� ������� � � � ���������� ������� ������� � ��� !�"� ��� �� ��� �� # $ !"� �������� �������� �������� %$� �"� �������� �����&�� �������� ���$' � �"$ !'������� �������� ��������� ( ��"������� ��������� �����)�� � * ������� �����)�� ��������� +� ��� ������� �������� �������� B. M. Ahmed et al. 41 R A D IA T IO N M E D IC IN E A N D O N C O L O G Y IJMMR 2015 Vol. 1 No. 1 phenotype profile of ALL (P>0.05). Because of the small ALL sample, expressing CD56, the analysis of results of these cases questions its statistical reliability. No significant association was detected between CD56 positive expression and age (P=0.806) (Table 2), gender, clinical or hematological data in AML patients (Table 3). Similarly, we could not associate this marker expression with cytogenetics risk groups (P=0.118) (Table 4). AML cases showed a statistically significant association between CD56 positivity and poor outcome. We missed one case and only 19 patients were evaluated including nine CD56 positive and Table 2. Association studies between CD56 and age in AML patients ��������� ��� ���� ��������� ��� ��� ��� �������� ��� ����� ��� � � ��� ������������� � !�� �"!##� "!"�� "!$"��� ��� ��������� ���� ������ ��������� ���� ����� � �� �� �� �� � ��� � �� ���� �� �� ������ �� ������ ������ ������� ������� �� �� ������ �� ������ � � � � ��� ������ !� !!�!"� ������ ������� ���#���$� %� �� ����� �� ������ � � � � �� "��"�� �� ������ &��&�� ������� ����'(���� %� �� �"��"� �� ������ � � � � "� !��!&� "� ""�"�� ��"�"� ������� ���#��� %� &� �!��!� �� ������ � � � � �� ������ &� &&�&&� ��&�&� ���!��� �����((�$� %� �� ������ �� ����!� � � � � !� �&���� �� ������ ���&�� ������� �������$� %� �� &��&�� �� ������ � � � � �� "��"�� �� ����!� ������ ����!�� ���)(��*���� %� �� �"��"� &� &&�&&� � � � +��� �� "��"�� "� ""�"�� ������ ������� ���,-� ���� �� �"��"� �� ������ � � � +��� "� !��!&� �� ������ ������ ��&��� ���.) � ���� &� �!��!� �� ������ � � � +���� �� "��"�� !� !!�!"� ������ ������� ����#/� ����� �� �"��"� �� ������ � � � +��� �� ������ �� ������ ������ ������� ����)�)(����� ���� �� ������ �� ������ � � � +!�� �� ������ �� ������ ������ ������� ���)��)(����� �!�� �� ������ �� ������ � � � Table 3. Association studies between CD56 expression and gender, clinical and hematological data in AML patients n: number of cases, Hb: hemoglobin, WBC: white blood counts, PLT: platelets count, PB: peripheral blood, BM: bone marrow Sig: significant, NS: non-significant. ��������� ���� ������ ��������� ��� ����� ��� �� ���� � �� �� �� �� � � � ����� �� ������ �� ������ ���!"������� #� ������ �� ������ $��������%� &��'��!�()� ���!� �� *��*�� +� +� #����� +�**�,� ��� Table 4.Association between cytogenetics risk groups and CD56 expression in AML patients *2 cultures failed, n: number, Sig: significant, NS: non-significant n = number of cases, NS: non-significant. B. M. Ahmed et al. 42 R A D IA T IO N M E D IC IN E A N D O N C O L O G Y IJMMR 2015 Vol. 1 No. 1 10 negative cases. Six patients out of the 9 positive CD56 cases (66.7 %) relapsed and only 3 (33.7 %) developed remission. Five (55.6%) of the CD56 expressing patients died. On the other hand, the CD56 negative patients group showed one (10 %) case relapse and death, while nine (90 %) patients developed remission. Statistical comparison between those patient with CD56 expression and those without showed significant increased incidence of relapse (P=0.01) (Table 5, Figure 1) and deaths (P=0.032) among patients expressing CD56 (Table 5, Figure 2). Discussion Acute leukemia comprises a heterogeneous group of diseases that differ in their etiology, pathogenesis, and prognosis. Our study investigated the prognostic significance of CD56 expression in these cases to evaluate its association with other prognostic factors, and its influence on the outcome during induction therapy. CD56 positivity was observed in 45 % of AML cases, and 10 % ALL cases. These results are in concordance with Fischer et al. [18] who reported that CD56 expression was not restricted to AML samples and could be detected in both B-cell and T-cell ALLs (14 %) as well. They concluded that it is not reliable for lineage distinction between AML and ALL. However, Montero et al. [19] reported exp- ression of this marker in only 4 patients (2 %) out of 200 ALL cases. These differences could be explained by lower number of cases in our study as compared to 200 cases studies, or due to methodology variation. The study of Fischer et al. [18] investigated CD56 in 452 newly diagnosed T-ALL patients included in the GMALL trial. The marker was expressed in 13.9 % of patients, predominating in the non-thymic subtypes, whereas thymic T-ALL was most common in the CD56 negative group. In addi- tion, the authors reported that CD56 expression was associated with higher resistance to therapy. Our statistical analysis showed that CD56 expression in AML cases was not associated with age (Table 2), sex, or any laboratory variables in- cluding blasts counts, WBC, hemoglobin concen- tration or platelets counts (Table 3). Similarly Yang et al. [20] could not associate CD56 expression with any laboratory variables in AML cases. However, other investigators [1] reported a higher proportion of CD56 expression in men. The presence of lymphadenopathy, hepato- megaly, and splenomegaly provide an indirect measurement of leukemic cell burden. We could not detect significant association of positive CD56 and presence of any of these clinical conditions in AML cases. Also, no significant association was found with other clinical features as presence of fever, pallor or bleeding tendency (Table 3). These findings are compatible with other published data (Table 18, 21). Our work detected only two cases of ALL expressing CD56, these were of B-ALL subtype and were not characterised by hepatomegaly or spleno- megaly. Although Ravandiet al. [6] considered that Table 5. Association between treatment outcome, fate and CD56 expression in AML patients n = number of cases, *= one case was missed. Fig. 1: Association between CD56 expression and treatment outcome in AML patients. Fig. 2. Association between CD56 expression and mortalityin AML patients ��������� ��� ����� ��������� ��� ��� ��� �� ��� ����� ��� � � �� � �� �������� � �� ��� �� ����� � ������ ��!�"��� �� ��� �� ����� ������� ������� ��� ����� �� #!���� �� ��� $� $$�$� %���� ��&� �� ��� �� ����� $��$�'� ����(�� ��� ����� �� B. M. Ahmed et al. 43 R A D IA T IO N M E D IC IN E A N D O N C O L O G Y IJMMR 2015 Vol. 1 No. 1 CD56 expression predicts occurrence of CNS dise- ase in ALL, none of our positive CD56 ALL cases had CNS involvement. In addition, no association was found between CD56 expression and demo- graphic, clinical presentation or laboratory tests (P>0.05). However, the low number of ALL cases expressing CD56 incapacitated our statistical and association analysis and doubts these results. CD56 expression was heterogeneous in different FAB subtypes. The more frequent CD56 expression was observed in M1 (35 %) and M2 (35 %). Allegrettiet al. [1] detected highest incidence of CD56 positivity among FAB subtypes M4 and M5, while Di Bona et al. [22] found more CD56 expression in M5 patients. These differences could be attributed to different number of patients in sample. To elucidate the prognostic value of CD56, its expression was studied in relation to treatment response in our AML patients. CD56 expression was shown to be significantly related to response to chemotherapy with higher relapse (66.6 % vs 10 %, P=0.010) and death rate (55.5 % vs 10 %, P=0.32) among patients with positive CD56 expression as compared to patients without it. The investigation [1] in a single center in Brazil that investigated cohort of 48 AML patients supported our results and documented the association of CD56 expression with worse prognosis. The authors observed higher death rate during induction in the CD56 positive cases. Their study detected short OS among cases with positive CD56 expression compared to CD56 negative patients. Similarly, Baer et al. stated that CD56 expression was significantly correlated with a short complete remission (CR) period and low OS [21].On the contrary, Ferrara et al. reported that there was no association between CD56 expression and the rate of CR in patients with AML [12]. Moreover, Di Bona et al. failed to demonstrate the influence of CD56 positivity on CR duration or OS in 171 studied cases of AML [22]. AML with t(8;21) is considered a group with favorable outcome, usually marked by high CR rate and prolonged disease-free survival. We encoun- tered five cases with this subtype (25 %), three of these patients (60 %) expressed CD56 and they relapsed and died. Although the small number of our cases (n=5) questions the significance of these results, the fatal outcome is too striking to be ignored. A previous large-scale studies investigated 144 AML patients with t(8;21) in the JALSGAML97 study. Univariate analysis showed that increased white blood cell counts (WBC�20�109/L),CD19 negativity, and CD56 positivity were critical adverse factors for relapse after CR. Multivariate analysis showed that WBC count and CD56 expression were independent adverse risk factors. The authors concluded that CD56 expression has a possible role in risks tratifi- cation for patients with AML with t(8;21) [23]. Our study included only four cases of promyelo- cytic leukemia (APL), three of these patients ex- pressed CD56 (75%). Relapses were evident in two (50%) of those cases expressing this marker. The clinical significance of CD56 expression was studied in a large series of patients with APL, treated with all-trans retinoic acid and anthracycline-based protocols. The authors documented that expression of CD56 is an independent adverse prognostic factor for relapse in these patients and suggested imple- menting this marker as a risk-adapted therapeutic strategies in APL [24]. Conclusions The association between CD56 expression and the poor response of AML to current treatments is not fully understood. Raspadori et al. [25] hypo- thesized that CD56+ AML blasts might overexpress p-glycoprotein (PGP), a multidrug-resistance (MDR) related protein, and reduce responsiveness to chemotherapy. Their data underlined the indepen- dent negative prognostic role of CD56 and PGP expression in cases of acute myeloid leukemia. In contrast, other investigators [26] showed that CD56 expression did not correlate with PGP expression, function, or with expression of the other MDR pro- teins. Other authors [27] have shown that CD56 expression by AML cells is positively regulated by RUNX1 p48 and is negatively regulated by other splice variants. Their findings suggest that p48 and RUNX1-driven NF-B and bcl2 pathways are new elements for targeted treatments in high-risk CD56AMLs. References 1. Alegretti AP, Bittar CM, Bittencourt R, Piccoli AK, Schneider L, Silla LM, Bo SD, Xavier RM. The expression of CD56 antigen is associated with poor prognosis in patients with acute myeloid leukemia. Revistabrasileira de hematologia e hemoterapia 2011; 33: 202–206. 2. Syrjala M, Anttila VJ, Ruutu T, Jansson SE. Flow cytometric detection of residual disease in acute leukemia by assaying blasts co-expressing myeloid and lymphatic antigens. Leukemia 1994; 8: 1564–1570. 3. Schabath R, Ratei R, Ludwig WD. The prognostic significance of antigen expression in leukaemia. Best Pract Res ClinHaematol 2003; 16(4): 613–628. 4. Lanier LL, Le AM, Civin CI, et al. The relationship of CD16 (Leu-11) and Leu-19 (NKH-1) antigen expression B. M. Ahmed et al. 44 R A D IA T IO N M E D IC IN E A N D O N C O L O G Y IJMMR 2015 Vol. 1 No. 1 on human peripheral blood NK cells and cytotoxic T lymphocytes. J Immunol 1986; 136: 4480–4486. 5. Chang H, Brandwein J, Yi QL, Chun K, Patterson B, Brien B.Extramedullary infiltrates of AML are associated with CD56 expression, 11q23 abnormalities and inferior clinical outcome. Leuk Res 2004; 28 (10): 1007–1011. 6. Ravandi F, Cortes J, Estrov Z, Thomas D, Giles FJ, Huh YO, et al. CD56 expression predicts occurrence of CNS disease in acute lymphoblastic leukemia. Leuk Res 2002; 26 (7): 643–649. 7. Suzuki R, Kagami Y, Takeuchi K, Kami M, Oka- moto M, Ichinohasama R, et al. Prognostic significance of CD56 expression for ALK-positive and ALK-negative anaplastic large-cell lymphoma of T/null cell phenotype. Blood 2000; 96 (9): 2993–3000. 8. Cook G, Dumbar M, Franklin IM. The role of adhesion molecules in multiple myeloma. ActaHaematol 1997; 97 (1–2): 81–89. 9. Tiftik N, Bolaman Z, Batun S, Ayyildiz O, Isikdogan A, Kadikoylu G, Muftuoglu E. The importance of CD7 and CD56 antigens in acute leukaemias 2004; 58(2): 149–152. 10. Murray CK, Estey E, Paietta E, Howard RS, Edenfield WJ, Pierce S, et al. CD56 expression in acute promyelocytic leukemia: a possible indicator of poor treatment outcome? J Clin Oncol 1999; 17 (1): 293–297. 11. Raspadori D, Damiani D, Lenoci M, Rondelli D, Testoni N, Nardi G, et al. CD56 antigenic expression in acute myeloid leukemia identifies patients with poor clinical prognosis. Leukemia 2001; 15 (8): 1161–1164. 12. Ferrara F, Morabito F, Martino B, Specchia G, Liso V, Nobile F, et al. CD56 expression is an indicator of poor clinical outcome in patients with acute promyelocytic leukemia treated withsimultaneous all-trans-retinoic acid and chemotherapy. J Clin Oncol 2000; 18 (6): 1295–1300. 13. Chang H, Salma F, Yi QL, Patterson B, Brien B, Minden MD. Prognostic relevance of immunophenotyping in 379 patients with acute myeloid leukemia. Leuk Res 2004; 28 (1): 43–48. 14. Swerdlow SH, Campo E, Harris NL, et al. (eds.) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues Lyon: IARC; 2008. 15. Bennet JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, Sultan C. Proposals for the classification of acutemyeloidleukemias. Br J Haematol 1976; 33: 451–458. 16. Jennings CD, Foon KA. Recent advances in flow cytometry: application to the diagnosis of hematologic malignancy. Blood 1997; 90: 2863–2892. 17. Shaffer LG, Tommerup N ISCN 2005: an Inter- national System for Human Cytogenetic Nomenclature. Basal. Karger Publishers; 2005. 18. Fischer L, Gokbuget N, Schwartz S, Burmeister T, Rieder H, Bruggemann M, Hoelzer D, and Thiel E. CD56 expression in T-cell acute lymphoblastic leukemia is associated with non-thymic phenotype and resistance to induction therapy but no inferior survival after risk-adapted therapy. Haematologica 2009; 94 (2): 224–229. 19. Montero I, Rios E, Parody R, Perez-Hurtado JM, Martin-Noya A, Rodriguez JM. CD56 in T-cell acute lymphoblastic leukaemia: a malignant transformation of an early myeloid-lymphoid progenitor? Haematologica 2003; 88 (9): E127–E128. 20. Yang DH, Lee JJ, Mun YC, Shin HJ, Kim YK, Cho SH, Chung IJ, Seong CM, Kim HJ. Predictable prognostic factor of CD56 expression in patients with acute myeloid leukemia with t(8:21) after high dose cytarabine or allogeneic hematopoietic stem cell transplantation. Am J Hematol 2007; 82: 1–5 21. Baer MR, Stewart CC, Lawrence D, Arthur DC, Byrd JC, Davey FR, Schiffer CA, Bloomfield CD. Expres- sion of the neural cell adhesion molecule CD56 is associated with short remission duration and survival in acute myeloid leukemia with t(8;21)(q22;q22). Blood 1997; 90: 1643–1648. 22. Di Bona E, Sartori R, Zambello R, Guercini N, Madeo D, Rodeghiero F. Prognostic significance of CD56 antigen expression in acute myeloid leukemia. Haema- tologica 2002; 87: 250–256. 23. Iriyama N, Hatta Y, Takeuchi J, Ogawa Y, Ohtake S, Sakura T, Mitani K, Ishida F, Takahashi M, Maeda T, Izumi T, Sakamaki H, Miyawaki S, Honda S, Miyazaki Y, Taki T, Taniwaki M, Naoe T. CD56 expression is an independent prognostic factor for relapse in acute myeloid leukemia with t(8;21). Leuk Res 2013; 37: 1021– 1026. 24. Montesinos P, Rayon C, Vellenga E, Brunet S, Gonzalez J, Gonzalez M, et al. Clinical significance of CD56 expression in patients with acute promyelocytic leu- kemia treated with all-trans retinoic acid and anthracyc- line-based regimens. Blood 2011; 117: 1799–1805. 25. Raspadori D, Lenoci M, Rondelli D, Testoni N, Nardi G, Sestigiani C. CD56 antigenic expression in acute myeloid leukemia identifies patients with poor clinical prognosis. Leukemia 2001; 15: 1161–1164. 26. Suvannasankha A, Minderman H, O’Loughlin KL, Sait SN, Stewart CC, Greco WR, Baer MR. Expression of the neural cell adhesion molecule CD56 is not asso- ciated with P-glycoprotein overexpression in core-binding factor acute myeloid leukemia. Leuk Res 2004; 28: 449– 455. 27. Gattenloehner S, Chuvpilo S, Langebrake C, Dirk Reinhardt D, Muller-Hermelink H, Serfling E, Vincent A, Marx A. Novel RUNX1 isoforms determine the fate of acute myeloid leukemia. Blood 2007; 110: 2027–2033. Received: 2014. 02.26 B. M. Ahmed et al.