Study on activation of AKT/mTOR pathway in anaplastic large cell lymphoma / 中华血液学杂志

<p><b>OBJECTIVE</b>To study the expression of anaplastic lymphoma kinase (ALK) and the phosphorylation status of AKT, mammalian target of rapamycin (mTOR), 4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase (p70S6K) and their interrelationships and clinical pathological significance in anaplastic large cell lymphoma (ALCL) patients.</p><p><b>METHODS</b>Immunohistochemical and EnVision methods were used to detect the expression of ALK, p-AKT, p-mTOR, p-4E-BP1 and p-p70S6K.</p><p><b>RESULTS</b>Among the 81 ALCL patients, 51 (63.0%) expressed ALK, whereas the other 30 (37.0%) did not. Patients with ALK(+) ALCL had a better prognosis than those with ALK-ALCL (P < 0.05). Out of the 71 ALCL samples studied, p-AKT was detected in 54 (76.1%) samples and its phosphorylation was correlated with ALK expression (P < 0.05); p-mTOR was detected in 57 (80.3%) samples and its expression was correlated with both ALK and p-AKT (P < 0.05); p-4E-BP1 and p-p70S6K were detected in 64 (90.1%) and 66 (93.0%) samples respectively, and their expressions were related with p-mTOR (P < 0.05), but not with ALK or p-AKT (P > 0.05). COX Proportional Hazard Model analysis showed that both the expression of ALK and the B symptoms affected the prognosis (P < 0.05), moreover, the former had greater impact than the later.</p><p><b>CONCLUSION</b>Expressions of p-AKT, p-mTOR, p-4E-BP1 and p-p70S6K are detected in ALCL, while ALK(+) cases have higher incidence than those with ALK(-) cases. Phosphorylation of AKT and mTOR is correlated with ALK expression, suggesting that there is an activated pathway of AKT/mTOR in patients with ALK(+) ALCL, but the activation have no obvious prognostic significance.</p>

Blockage of mTOR signaling pathway by rapamycin contributes to inhibition of tumor cell proliferation in ALK-positive lymphoid cell strains / 中华血液学杂志

<p><b>OBJECTIVE</b>To investigate the relationship between mTOR signaling pathway and ALK-positive lymphoid cell lines.</p><p><b>METHODS</b>The expression of the downstream effector proteins of mTOR were analyzed by Western blot before and after Karpas299, BaF3/NPM-ALK and BaF3 cell lines treated with rapamycin. Effect of rapamycin on cell proliferation was detected by MTT assay. FACS was used to analyze apoptosis and cell cycles.</p><p><b>RESULTS</b>mTOR signaling phosphoproteins, p-p70S6K and p-4E-BP1 were highly expressed in ALK(+) Karpas299, BaF3/NPM-ALK and parental BaF3 cell lines, and they were dephosphorylated after 1 h withdrawal of IL-3 in BaF3 cells. After 48 h exposure to 10 nmol/L rapamycin, p-p70S6K and p-4E-BP1 proteins expression were decreased, and mainly for the former. The relative inhibitory rate to its control cells was 24.4% in Karpas299, 37.8% in BaF3/NPM-ALK and 61.6% in BaF3. The apoptotic ratio was increased from (11.97 +/- 0.11)% to (15.87 +/- 0.62)% in Karpas299 (P < 0.05), from (3.23 +/- 0.11)% to (7.67 +/- 0.49)% in BaF3 (P < 0.05) and from (1.90 +/- 0.47)% to (2.80 +/- 0.27)% in BaF3/NPM-ALK (P > 0.05). The fraction of G(1) phase cells increased from (37.63 +/- 1.91)% to (69.77 +/- 5.44)% in BaF3/NPM-ALK, from (31.13 +/- 2.51)% to (40.70 +/- 1.47)% in Karpas299 and (53.57 +/- 2.22)% to (63.70 +/- 1.20)% in BaF3 (P < 0.05).</p><p><b>CONCLUSION</b>NPM-ALK kinase can activate mTOR signaling pathway. Rapamycin can inhibit the proliferation of ALK(+) lymphoid cells by blocking mTOR signaling pathway and inducing cell cycling arrest at G(1) phase.</p>

Expression of anaplastic lymphoma kinase and survivin proteins in anaplastic large cell lymphoma and its significance / 中华病理学杂志

<p><b>OBJECTIVE</b>To study the expression of anaplastic lymphoma kinase (ALK) and survivin proteins in anaplastic large cell lymphoma (ALCL) and there clinical significance.</p><p><b>METHODS</b>The morphologic characteristics were studied by routine light microscopy. Immunohistochemical staining for ALK and survivin proteins was performed using LSAB method.</p><p><b>RESULTS</b>ALK protein was positive in 51 cases (63%) and negative in 30 cases (37%) of the 81 cases of ALCL studied. The prognosis of patients with ALK protein expression was better than those without ALK expression (P < 0.05). As for survivin protein, there were various degrees of expression in all the 77 ALCL cases studied. High level of survivin protein expression was observed in 33 cases (42.9%), while low level of expression was seen in 44 cases (57.1%). The expression of survivin protein did not correlate with that of ALK protein (P > 0.05). The survival rate was significantly lower in patients with high survivin protein expression (P < 0.05). In cases with ALK protein expression, the prognosis was less favorable if there was also high co-expression of survivin protein (P < 0.05). In ALK protein negative cases, prognosis did not significantly correlate with the expression of survivin protein (P > 0.05). In addition, multivariate analysis confirmed the prognosis value of ALK protein expression, survivin protein expression and constitutional symptoms.</p><p><b>CONCLUSION</b>Survivin protein expression can serve as an independent prognostic predictor of unfavorable clinical outcome in patients with ALCL, especially when ALK protein is positive.</p>

Clinico-pathological analysis of 188 cases of bone marrow involvement of lymphoma / 中华血液学杂志

<p><b>OBJECTIVE</b>To evaluate pathomorphologic and immunohistochemical characteristics of the bone marrow involvement of lymphoma and its significance in the diagnosis and subtype of lymphoma with bone marrow involvement.</p><p><b>METHODS</b>One hundred and eighty eight formalin fixed and paraffin embedded bone marrow biopsy specimens were studied. Immunohistochemical staining was performed.</p><p><b>RESULTS</b>(1) Five patterns of bone marrow involvement of lymphoma were found, including diffuse (44.9%), focal (29.3%), interstitial (11.6%) and nodular (6.1%). (2) There were many subtypes of lymphoma in these cases, the most common type was lymphoplasmacytic lymphoma (21.7%). (3) The lymphomas in bone marrow biopsy had their own special characteristics of morphology and immunophenotype as did in extra-medullar lymphomas. (4) Fibrosis (75.8%) and hematopoietic tissue hypoplasia (71.1%) were found in most cases and necrosis in a few cases.</p><p><b>CONCLUSIONS</b>Most cases of bone marrow involvement of lymphoma could be diagnosed and classified by combination of histopathological and immunohistochemical analysis. Diagnosis of some cases could be made only after the review of pathological changes of lymph node. A few cases were difficult to classify their subtypes of lymphoma.</p>

A clinicopathological study of 96 cases of lymphoblastic lymphoma / 中华血液学杂志

<p><b>OBJECTIVE</b>To investigate the clinicopathological and immunohistochemical features of lymphoblastic lymphoma (LBL).</p><p><b>METHODS</b>A retrospective clinicopathological study of 96 cases LBL was carried out. Immunohistochemical staining was used for the characterization and immunophenotyping.</p><p><b>RESULTS</b>The patients age ranged from 4 to 72 years, with a median of 16 years, 69 patients were male and 27 female. Seventy-three cases had superficial or multi-lymphoadenopathy and 31 of them had mediastinal masses. Bone marrow was involved in 15 cases. Seventy-three cases were in clinical stages III and IV. The median survival of the followed-up patients was 5.5 (2 approximately 120) months. TdT and CD99 positive reactions were 75.0% and 92.7%, respectively. Of the 96 cases, 78 displayed T-cell marker positivity and 18 B-cell markers. 82.1% of the patients younger than 30 years of age had significantly higher incidences of T-LBL (64 patients), and 93.6% of the patients with mediastinal masses expressed T-cell markers. The poor prognostic factors were T-cell tumors, clinical stages III and IV, Ki-67 PI < 80% and no chemotherapy (P < 0.01).</p><p><b>CONCLUSION</b>In children and young males, mediastinal masses with superficial or multi-lymphoadenopathy favors the diagnosis of LBL, but negative TdT reaction can not exclude this diagnosis. T-LBL is more common than B-LBL. Clinical stages, immunophenotypes and the level of Ki-67 expression were closely related with prognosis of LBL.</p>