CD34 expression is associated with poor clinical outcome in patients with acute promyelocytic leukemia

This study investigated the clinical characteristics and prognostic relevance of CD34 expression in 47 patients with acute promyelocytic leukemia (APL), showing t(15;17) or PML/RARalpha. Ten (21.3%) of the APL patients were CD34(+). CD34 expression was associated with hypogranular morphology (P = 0.002) and hyperleukocytosis (P = 0.015). However, there were no statistically significant differences in age, sex, hemoglobin level, platelet count, or percentage of blasts between the CD34(+) and CD34(-) APL groups. Multiplex RT-PCR analysis showed that the L-form (BCR1) and S-form (BCR3) were correlated with CD34(-) APL and CD34(+) APL, respectively. Despite the lack of a difference in the complete remission rate, overall survival (OS) and disease-free survival (DFS) were significantly lower in the CD34(+) group than in the CD34(-) group (P = 0.012 and P = 0.0051, respectively). By multivariate analysis, the CD34(+) group showed a significant independent variable in DFS compared with the CD34(-) group, but this was not demonstrated for OS. In conclusion, CD34 expression in APL is a unique clinical feature associated with leukocytosis and atypical morphology with hypogranular pattern and is associated with a poor clinical outcome.     

Prognostic impact of CD200 and CD56 expression in adult acute lymphoblastic leukemia patients

Background: The aim of the study is to determine the prognostic relevance of CD200/ CD56 expression in adult acute lymphoblastic leukemia patients.

Methods: The expression of CD200 and CD56 by blast cells was assessed by flow cytometry before the start of chemotherapy in 70 B-ALL patients.

Results: Positive expression of CD200 was detected in forty-six patients (66%) and CD56 was detected in 7 patients (10%) out of 70 patients, respectively. Only three patients (4.3%) had co-expression for CD200⁺ and CD56⁺. Splenomegaly and thrombocytopenia were frequently observed more in CD200⁺ patients. Increased frequency of CD34⁺ was associated with CD200⁺and CD56⁺ patients. The CD200⁺ and CD56⁺ subgroups of B-ALL patients had inferior OS and disease free survival compared to CD 200^? and CD 56^? patients.

Conclusions: CD200⁺ and/or CD56⁺ positive expression in B-ALL patients at diagnosis is a poor prognostic biomarker. Identification of CD200⁺ and CD56⁺ expression at diagnosis is recommended for a better stratification of adult B-ALL patients.     

Phenotypic and clinical heterogeneity of CD56-positive acute nonlymphoblastic leukemia

Summary The precise phenotype and clinical course are described of a subgroup of acute nonlymphoblastic leukemias (ANLL) expressing the NK-cell differentiation antigen CD56. As previously reported, CD56+ leukemias occurred in a frequency of about 20% of ANLL cases showing clinical and immunophenotypical heterogeneity. Carrying various myelomonocytic markers, all cases were diagnosed to be of nonlymphoid origin. Positive or negative expression of CD34 allowed us to distinguish two major subtypes of CD56+ leukemias representing immature and more differentiated cells carrying further differentiation antigens (CD14 and/or CD15) of the myelomonocytic lineages. These phenotypes correlated with the M0, M2, M4, and M5 leukemias of the FAB classification.     

CD34-positive acute promyelocytic leukemia is associated with leukocytosis, microgranular/hypogranular morphology, expression of CD2 and bcr3 isoform

Acute promyelocytic leukemia (APL) has a favorable prognosis. Current therapy includes chemotherapy used in combination with all-trans-retinoic acid (ATRA). Although the differentiating effects of ATRA on promyelocytes have been well established, in vitro studies have shown that less-differentiated APL blasts (CD34(+)) demonstrate a variable responsiveness to ATRA. To assess the clinical relevance of this finding, we analyzed a cohort of 38 patients with t(15;17) and/or PML-RARalpha APL to determine the incidence and laboratory features of CD34(+) APL. Thirty-two percent (12/38) of cases were CD34(+). There was a difference in WBC at presentation between CD34(+) and CD34(-) cases (34.6 +/- 9.2, mean +/- standard error vs. 5.4 +/- 2.0, P = 0.009). Patients with CD34(+) APL demonstrated a micro/hypogranular phenotype (75%) (P = 0.001), co-expression of CD2(+) (83%) (P = 0.001), and the bcr3 isoform (100%) (P = 0.017). In contrast, CD34(-) cases demonstrated hypergranular morphology (65%), CD2(+) (15%), and the bcr1 isoform (50%). A high presenting WBC count (\G10 x 10(9)/L) was associated with an inferior overall survival (Log rank = 0.0047). Patients with CD34(+) APL demonstrated an incidence of early mortality of 50%. Despite a marked correlation between CD34 positivity and increased WBC count, overall survival of CD34(+) and CD34(-) cases did not differ significantly in our small cohort. Immunophenotypic analysis for CD34 expression should be included in future large APL trials to determine if detection of CD34(+) blasts represents an independent adverse prognostic factor.     

CD56 expression in myeloperoxidase-negative FAB M5 acute myeloid leukemia

CD56 is a natural killer (NK) cell marker that has been identified in approximately 15-20% of acute myeloid leukemia (AML) cases, where it has been associated with monocytic morphology and chromosomal abnormalities such as trisomy 8, t(8;21), t(15;17), and 11q23 rearrangements. The clinical presentation, chromosomal abnormalities as detected by fluorescent in-situ hybridization (FISH), and clinical outcomes of 7 patients with AML are presented. These cases were characterized by French-American-British (FAB) M5 morphology, myeloperoxidase (MPO) negativity, and co-expression of myelomonocytic and NK cell-associated antigens (CD11c(+), CD13(+), CD15(+), CD33(+), HLA-DR(+), and CD56(+)). All patients presented lymph node, hepatic, or splenic involvement at diagnosis. Despite the homogeneous morphologic and immunophenotypic characteristics the outcomes varied considerably. Two patients died during induction therapy, but the other five patients attained complete remission (CR). Of these five patients, 4 have received a bone marrow transplantation (autologous or allogeneic) and 3 of them are in CR (median follow-up: 45 months). The three patients with 11q23 rearrangements had a poor outcome and died of their disease within 1 year of diagnosis. Further studies with a larger group of patients would help establish the actual prognostic value of these morphologic, immunophenotypic and cytogenetic features.     

CD7+CD56+双阳性急性髓系白血病临床生物学特征

目的：探讨CD7^＋CD56^＋急性髓系白血病（AML）的临床生物学意义。方法：对25例初治CD7^＋CD56^＋AML患者进行细胞学形态、免疫表型、多药耐药P糖蛋白（PgP）检测，临床观察、并常规采用HAE方案诱导治疗，判定疗效，并随机选择66例CD7^-CD56^-AML患者进行对照。结果：CD7^＋CD56^＋AML阳性率4．08％（25／612）。CD7^＋CD56^＋AML在FAB分型中以M0、M1、M5、M7多见。与CD7^-CD56^-AML组比较CD7^＋CD56^＋AML具有高血红蛋白含量（89．29：75．62g／L，P〈0．05），高表达PgP（78．26％：34．85％，P〈0．01）和CD34表达（72．00％：45．45％，P〈0．05）等特征；此外，CD7^＋CD56^＋AML患者中枢神经系统浸润现象明显（36．00％：3．27％，P〈0．01），CD7CD56共表达与年龄、性别、白细胞计数、血小板计数、及外周血幼稚细胞数无关，也不影响完全缓解率和无病生存时间（均P〉0．05）。结论：CD7^＋CD56^＋AML具有独特的临床生物学特征，较少贫血，高表达PgP和CD34，常伴有中枢神经系统浸润。     

Expression of CD56 is a risk factor for acute lymphocytic leukemia with central nervous system involvement in adults

Objective: To gain further insights into the predisposing risk factors for central nervous system (CNS) involvement in patients with acute lymphocytic leukemia (ALL), the impact of CD56 expression in these patients was investigated.

Methods: We reviewed the clinical features of CD56 expression in 588 consecutive ALL patients treated with systemic chemotherapy regimens between 2000 and 2014. The categorical data from CD56⁺ ALL patients were compared with those from CD56^? ALL patients.

Results: Among the 588 patients studied, 18.9% showed CD56 expression. The expression was significantly associated with CD33⁺, CD10^?, CD15⁺, TdT^?, and CD5⁺ immunophenotypes. After systemic chemotherapy, 8.8% patients showed CNS involvement, of which 3.2% exhibited combined recurrences and 5.6% exhibited isolated CNS involvement. The 5-year event-free survival was significantly lower for patients with CD56⁺ immunophenotype compared with patients with CD56^? immunophenotype (22.5% vs. 32.7%, P?=?0.04). Cumulative incidences of CNS involvement were significantly greater in the CD56⁺ cohort compared with the CD56^? cohort (14.4% vs. 7.5%, P?=?0.02). Multivariate analysis revealed CD56 expression to be statistically significant risk factors for CNS involvement.

Conclusion: CD56 expression should be regarded as an independent risk factor for ALL with CNS involvement in adults.     

Clonal development from a progenitor with restricted differentiative expression in acute lymphoblastic leukemia

Three patients with acute lymphoblastic leukemia (ALL) and heterozygous for the Mediterranean variant of glucose-6-phosphate dehydrogenase (G6PD) have been investigated with the 2-deoxyglucose-6-phosphate (2dG6P) method to determine the number and type of progenitor cells in which the disease arose. A monoclonal origin was established for the lymphoblasts, while the other hemopoietic cell lines were not involved in the leukemic process.     

Differential expression of CD56 and CD44 in the evolution of extramedullary myeloma

We report on the different expression of CD56 and CD44 in plasma cells (PCs) simultaneously collected from bone marrow, extramedullary locations and peripheral blood in seven patients with multiple myeloma. Extramedullary PCs showed absence of CD56. In the bone marrow, however, subsets with varying CD56 expression were found in five out of seven patients, with one subset corresponding to that of extramedullar PCs. This differs from the de novo downregulation of CD56 in PC leukaemia, and suggests different mechanisms of spread of myeloma cells. CD44 expression was generally upregulated on extramedullary PCs. In three of the patients we investigated the clonal origin of extramedullary myeloma cells by sequencing the variable portion of the heavy chain immunoglobulin gene in phenotypically defined PCs isolated from different locations. In each patient we found malignant PCs with different homing behaviour originating from a common precursor cell.     

Prognostic significance of CD7+CD56+ phenotype and chromosome 5 abnormalities for acute myeloid leukemia M0

Myeloid/natural killer (NK) cell precursor acute leukemia is an entity of acute leukemia characterized by poor prognosis and a CD7+CD56+ myeloid antigen+ phenotype without light-microscopic myeloperoxidase reactivity. This disease shares several clinical characteristics with acute myeloid leukemia (AML) M0. To clarify the relationship between these 2 leukemias, we analyzed 105 cases of AML M0. Among them, 17 were CD7+ and CD56+, 77 were negative for either antigen, and 11 could not be determined. CD7+CD56+ AML M0 showed onset at significantly lower patient age (median 46 versus 63 years, P = .004). The disease localization and the hematological manifestations were significantly different: CD7+CD56+ AML showed more frequent extramedullary involvement, fewer circulating leukemic blasts, less anemia, and less thrombocytopenia than did AML M0. The cytogenetic aberrations were also unique, because no 5q abnormalities were found in CD7+CD56+ M0. The prognosis of CD7+CD56+ M0 was poor in patients younger than 46 years (P = .03). Multivariate analysis showed that the CD7+CD56+ phenotype was a significant prognostic factor for AML M0, as well as age, circulating blast percentage, and chromosome 5 abnormalities These findings suggest that AML M0 consists of heterogeneous subgroups to be managed separately, and CD7+CD56+ M0 constitutes a distinct subtype of AML M0.     

Clonal evolution as judged by immunoglobulin heavy chain gene rearrangements in relapsing precursor-B acute lymphoblastic leukemia.

Oligoclonality and ongoing clonal evolution are common features in patients with precursor-B (pre-B) acute lymphoblastic leukemia (ALL), as judged by immunoglobulin heavy chain (IgH) gene rearrangement analysis. These features are considered to be results of secondary rearrangements after malignant transformation or emergence of new tumor clones. In the present study we analyzed the IgH gene rearrangement status in 18 cases with relapsing pre-B ALL using variable heavy chain (V(H)) gene family specific polymerase chain reaction (PCR) amplification and single stranded conformation polymorphism (SSCP) analysis. Clonal IgH rearrangements were displayed in all leukemias but one, and altered rearrangement patterns occurred in five cases (29%), which were selected for detailed nucleotide sequence analysis. In one case, multiple subclones at diagnosis were suggested to be derived from a progenitor clone through joining of different V(H) germline gene segments to a pre-existing D-J(H) complex (V(H) to D-J(H) joining). Evidence for V(H) gene replacement with identical N-sequences at the V(H)-D junction and a common D-J(H) region was observed in one case. Diversification at the V(H)-D junction consisting of heterogeneous N-sequences were observed in one case. This molecular modification of the V(H)-D region could fit a hypothesized "open-and-shut" mechanism. Nevertheless, despite these ongoing events at least one IgH rearrangement remained unchanged throughout the disease in most patients, indicating that the immunoglobulin heavy chain locus can be a suitable marker for detection of minimal residual disease (MRD).     

Cerebellar myeloblastoma formation in CD7-positive, neural cell adhesion molecule (CD56)-positive acute myelogenous leukemia (M1)

 We present a first report of a CD7⁺ acute myelogenous leukemia patient who developed intracranial myeloblastomas. The patient was neurologically normal on physical examination at presentation. The peripheral leukocyte count was extremely high (203.6×10⁹/l). The blasts expressed CD7 and CD56 (neural cell adhesion molecule) in addition to CD13, CD33, CD34, and HLA-DR. The karyotype of bone marrow cells was normal. The patient was diagnosed as having acute myelogenous leukemia (AML, M1). Following a short period of complete remission, bone marrow relapse and meningeal leukemia occurred, and the patient died of respiratory failure. Autopsy revealed that blasts had invaded the subarachnoid space and cerebellum, and two myeloblastomas were found in the cerebellar hemisphere. Both CD7⁺ and CD56⁺ AML have been reported to have a high incidence of central nervous system involvement. CD7⁺ CD56⁺ AML calls for prophylaxis of central nervous system leukemia. Received: 2 May 1997 / Accepted: 17 July 1997     

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

Background

Expression of CD56 has been associated with poor prognosis in acute myeloid leukemia and aggressive lymphoma.

Design and Methods

We analyzed the impact of CD56 expression in a cohort of 452 newly diagnosed adult T-cell acute lymphoblastic leukemia (T-ALL) patients; clinical data were available for 306 patients. Treatment was according to the GMALL study protocols 06/99 and 07/03 stipulating stratification into standard (thymic T-ALL) and high risk (pre- and mature T-ALL) groups.

Results

CD56 expression was detected in 63/452 (13.9%) patients. CD56⁺ T-ALL were predominantly of non-thymic (pre-T 35%, mature 41%) immunophenotypic subtypes, whereas 53% of the CD56⁻ cases were thymic T-ALL (p=0.00002). CD13, CD33, CD34 and HLA-DR were significantly more frequently expressed. A clonal T-cell receptor rearrangement was detected in 22/23 CD56⁺ ALL. No major clinical differences were observed at presentation. Treatment of CD56⁺ ALL resulted in a lower rate of complete remissions (70% vs. 88%) (p=0.001) and a higher rate of resistant disease (21% vs. 8%) (p=0.004). CD56 expression had no significant influence on overall (48% vs. 59%) and disease free survival (67% vs. 57%) at three years.

Conclusions

CD56 is expressed on a subset of adult T-ALL with distinct immunophenotypical features and higher resistance to therapy. Most CD56⁺ ALL were treated in the high-risk arm of the GMALL study protocols owing to their non-thymic phenotype. Thus after risk adapted treatment a prognostic impact of CD56 expression was not detectable.     

NK cell dysfunction with down‐regulated CD16 and up‐regulated CD56 molecules in patients with esophageal squamous cell carcinoma

NK cells can be divided into two subsets, CD56^dim and CD56^bright NK cells, based on their expression of CD56 and CD16. In the present study, we analyzed NK cell dysfunction in patients with esophageal squamous cell carcinoma (ESCC), with a particular focus on the expression of CD16 and CD56 molecules. Expression of CD16 and CD56, and the distribution of CD56^dim or CD56^bright NK cells gated on CD56(+)CD3(–) NK cells were compared between ESCC patients (n= 40) and healthy donors (n= 38). Purified NK cells were evaluated for Cetuximab‐mediated antibody‐dependent cellular cytotoxicity (ADCC) against epidermal growth factor receptor (EGFR)‐expressing ESCC cell lines. Although there were no significant differences in the distribution of CD56^dim and CD56^bright NK cells between ESCC patients and healthy donors, down‐regulated CD16 and up‐regulated CD56 were significantly observed on NK cells of ESCC patients, paralleling the impairment of Cetuximab‐mediated ADCC, in comparison with healthy donors. After patients received curative resections of ESCC, the down‐regulated CD16 and up‐regulated CD56 were significantly restored to the levels of healthy donors. Moreover, TGF‐beta1 partially contributed to down‐regulation of CD16 on NK cells. Down‐regulated CD16 and up‐regulated CD56 molecules on NK cells were observed in ESCC patients, resulting in NK cell dysfunction.     

CD25 as an adverse prognostic factor in elderly patients with acute myeloid leukemia

Objectives: CD25 has been reported to be highly expressed in leukemia stem cells and correlated with adverse outcomes in young patients with acute myeloid leukemia (AML). However, the significance of CD25 expression in elderly patients with AML has not yet been investigated.

Methods: We retrospectively analyzed 154 newly diagnosed AML patients aged 60 years or over by flow cytometry.

Results: CD25-positive AML was characterized by high white blood cell counts, secondary AML, rare favorable karyotypes, and positivity for CD34 and CD7 antigens, compared with CD25-negative AML. CD25 positivity was significantly correlated with an inferior complete remission (CR), event-free survival (EFS), and overall survival. Multivariate analysis showed CD25 positivity to be a significant prognostic predictor of CR and EFS. A regimen of low-dose cytarabine and aclarubicin combined with granulocyte-colony-stimulating factor (CAG) led to higher CR rates in the CD25-positive AML patients than intensive chemotherapies. CD25 expression was increased at relapse and in the development of leukemic status from myelodysplastic syndrome or myeloproliferative neoplasm.

Discussion: An effective treatment strategy for elderly patients with CD25-positive AML has not been established. Further studies are needed to evaluate the effect of a CAG regimen and allogenic stem cell transplantation in patients.

Conclusion: CD25 is an independent prognostic factor in elderly AML patients. Alternative therapies for CD25-positive elderly AML patients are needed.     

The presence of CD56/CD16 in T-cell acute lymphoblastic leukaemia correlates with the expression of cytotoxic molecules and is associated with worse response to treatment

Some cases of T-cell acute lymphoblastic leukaemia (ALL) express markers found in natural-killer (NK) cells, such as CD56 and CD16. Out of 84 T-cell ALL cases diagnosed at our Institution, CD56 and/or CD16 was detected in 24 (28·5%), which we designated T/NK-ALL group. Clinical features, laboratory characteristics, survival and expression of cytotoxic molecules were compared in T/NK-ALL and T-ALL patients. Significant differences were observed regarding age (24·9 vs. 16·4 years in T/NK-ALL and T-ALL, respectively, P  =   0·006) and platelet counts (177 × 10⁹/l vs. 75 × 10⁹/l in T/NK-ALL and T-ALL, respectively, P  =   0·03). Immunophenotypic analysis demonstrated that CD34, CD45RA and CD33 were more expressed in T/NK-ALL patients, whereas CD8 and terminal deoxynucleotidyl transferase were more expressed in T-ALL patients ( P  <   0·05 ) . The mean overall survival (863 vs. 1869 d, P  =   0·02) and disease-free survival (855 vs. 2095 d, P  =   0·002) were shorter in patients expressing CD56/CD16. However, multivariate analysis identified CD56/CD16 as an independent prognostic factor only for DFS. Cytotoxic molecules were highly expressed in T/NK-ALL compared to T-ALL. Perforin, granzyme B and TIA-1 were detected in 12/17, 4/17 and 7/24 T/NK-ALL patients and in 1/20, 0/20 and 1/20 T-ALL respectively ( P  <   0·001, P  =   0·036 and P  =   0·054). Therefore, the presence of CD56/CD16 was associated with distinct clinical features and expression of cytotoxic molecules in the blasts.     

CD56在急性单核细胞白血病细胞表达的意义

目的：探讨CD56分子对急性髓性白血病（AML）之急性单核细胞白血病（M5）细胞生物学及临床特征的影响.方法：应用G显带技术及流式细胞仪对45例M5患者分别进行核型及免疫表型检测，并回顾分析其临床资料.结果：45例患者中CD56表达阳性17例（37.78%），其中正常核型2例（11.76%），异常核型15例（88.24%），以8号三体和11q23异常易见（分别占23.53%，29.41%）;伴CD56抗原表达的患者高表达CD11b，CD14（P＜0.01，P＜0.05），外周血白细胞计数偏高，骨髓及外周血中原始和幼稚细胞百分比明显升高（P＜0.05），较多出现髓外浸润，尤其以淋巴结肿大（P＜0.05）和肝脾肿大（P＜0.05）明显，伴二系以上受累也明显高于对照组（P＜0.05），而中枢神经系统及皮肤浸润与对照组比较差异无统计学意义（P＞0.05），同时伴CD56阳性的患者出现较低的完全缓解率及较短的生存期（P＜0.05）.结论：CD56阳性的M5患者易出现异常核型，高表达CD11b，CD14，预后较差。     

Exclusive expression of G-CSF receptor on myeloid progenitors in bone marrow CD34+ cells

Although granulocyte colony-stimulating factor (G-CSF) has been reported to act on cells of neutrophilic lineage, the administration of G-CSF to induce the mobilization of various haematopoietic progenitors into the circulation. We analysed the expression of receptors for G-CSF (G-CSFR) on human bone marrow and G-CSF-mobilized peripheral blood CD34+ cells, and examined the proliferation and differentiation capabilities of sorted CD34+G-CSFR+ and CD34+G-CSFR- cells using methylcellulose clonal culture. Flow cytometric analysis showed that G-CSFR was expressed on 14.9 +/- 4.9% of bone marrow CD34+ cells, most of which were included in CD34+CD33+ and CD34+CD38+ cell fractions. In clonal cultures, CD34+G-CSFR+ cells produced only myeloid colonies, whereas CD34+G-CSFR- cells produced erythroid bursts, megakaryocyte and multilineage colonies. When incubated with the cytokine cocktail for 5 d, CD34+G-CSFR- cells generated CD34+G-CSFR+ myeloid progenitors. In G-CSF-mobilized peripheral blood, CD34+ cells contained 10.8 +/- 5.8% of G-CSFR+ cells, most of which were also myeloid progenitors, although CD34+G-CSFR- cells contained a substantial number of myeloid progenitors. These results indicated that the expression of G-CSFR on CD34+ cells is restricted to myeloid progenitors, suggesting that the specific activity of G-CSF on myelopoiesis depends on the exclusive expression of its receptor on myeloid progenitors, and that the mobilization of various haematopoietic progenitors is not a direct effect of G-CSF in humans.     

Aberrant co-expression of CD19 and CD56 as surrogate markers of acute myeloid leukemias with t(8;21) in Taiwan

Aberrant antigen expression in acute myeloid leukemia (AML) has been extensively studied in the West with limited reports from Taiwan. We carried out this retrospective study to characterize the frequency and significance of aberrant antigen expression of AML in Taiwan. Among 111 cases, 58 (52%) showed aberrant antigen expression, most frequently CD7 (27%) and CD56 (23%). Aberrant CD7 expression was observed in all non-AML-M3 subtypes, most frequently in AML-M7 (4/6, 67%); while CD19 expression was only observed in AML-M2 (5/36, 14%). CD56 expression was most common in AML-M5 (4/8, 50%). The relative frequency of CD19 and CD56 expression in AML with t(8;21) was higher than those with other chromosomal abnormalities or normal karyotype (P = 0.011 and 0.005, respectively). In non-M3 AML, aberrant antigen expression was identified in 56/96 (58%) cases, in contrast to 2/15 (13%) AML-M3 cases (P = 0.001). CD7, CD19 and CD56 expression was not correlated with remission rate. We concluded that aberrant immunophenotype was more frequent in non-M3 leukemias in Taiwan. The relative frequency of CD19 and/or CD56 expression in AML with t(8;21) was significantly higher than those without this translocation and co-expression of these two antigens may serve as the surrogate markers for AML with t(8;21).