CDK6: an attractive therapeutic target for T-ALL/LBL.

INTRODUCTION: Human T-cell acute lymphoblastic leukemia/T-cell lymphoblastic lymphoma (T-ALL/LBL) is a type of cancer that originates from the bone marrow and spreads quickly to other organs. Long-term survival rate with current available chemotherapy is less than 20%. Despite the potentially huge market, a truly effective and safe therapy for T-ALL/LBL is elusive. Thus, it is imperative to identify new therapeutic ways to target essential pathways in T-ALL that regulate the proliferation and survival of these cancer cells. AREAS COVERED: The role of the Cyclin-dependent kinase 6 (CDK6) pathway in human T-ALL is of significant interest with major clinical/translational relevance. This review covers the recent advances in elucidating the essential roles of CDK6 and its closely regulated networks in proliferation, survival, and metabolism of T-ALL cells, with new insight into its mechanisms of action which hopefully could trigger the identification of new therapeutic avenues. EXPERT OPINION: Animal models showed that inhibition of CDK6 and its related networks blocked initiation, growth, and survival of T-ALL in vivo. Numerous clinical trials of CDK4/6 inhibitors are ongoing in T-ALL. Specific CDK6 inhibitors alone or novel combination regimens may hopefully delay the progression, or even reverse the symptoms of T-ALL, leading to disease eradication and cure.

A Dual Role for FADD in Human Precursor T-Cell Neoplasms.

A reduction in FADD levels has been reported in precursor T-cell neoplasms and other tumor types. Such reduction would impact on the ability of tumor cells to undergo apoptosis and has been associated with poor clinical outcomes. However, FADD is also known to participate in non-apoptotic functions, but these mechanisms are not well-understood. Linking FADD expression to the severity of precursor T-cell neoplasms could indicate its use as a prognostic marker and may open new avenues for targeted therapeutic strategies. Using transcriptomic and clinical data from patients with precursor T-cell neoplasms, complemented by in vitro analysis of cellular functions and by high-throughput interactomics, our results allow us to propose a dual role for FADD in precursor T-cell neoplasms, whereby resisting cell death and chemotherapy would be a canonical consequence of FADD deficiency in these tumors, whereas deregulation of the cellular metabolism would be a relevant non-canonical function in patients expressing FADD. These results reveal that evaluation of FADD expression in precursor T-cell neoplasms may aid in the understanding of the biological processes that are affected in the tumor cells. The altered biological processes can be of different natures depending on the availability of FADD influencing its ability to exert its canonical or non-canonical functions. Accordingly, specific therapeutic interventions would be needed in each case.

[Long-term outcome of childhood T-cell acute lymphoblastic leukemia treated with modified national protocol of childhood leukemia in China-acute lymphoblastic leukemia 2008].

Objective: To analyse the long-term efficacy in childhood T-cell acute lymphoblastic leukemia (T-ALL) cases enrolled in the national protocol of childhood leukemia in China-acute lymphoblastic leukemia (NPCLC-ALL) 2008. Methods: Clinical data of 96 patients diagnosed as T-ALL and treated with NPCLC-ALL2008 protocol between January 2009 and December 2017 in the Department of Hematology-Oncology, the Children's Hospital, Zhejiang University School of Medicine were analyzed retrospectively. Predictive value of minimal residual disease (MRD) monitored by flow cytometry was analyzed. Kaplan-Meier method was used for long-term survival analysis. Results: A total of 96 evaluable patients with newly diagnosed T-ALL were analysed, including 72 males and 24 females. The age was 9.5 (ranged from 1.0 to 16.0) years. The follow-up time was 5.7 (ranged from 1.0 to 9.7) years. Among 96 patients, 92 (96%) achieved complete remission. The 5-year event free survival (EFS) and overall survival (OS) rates were (61±6) % and (70±5) %, respectively. Relapse occurred in 18 cases and the 5-year cumulative incidence of relapse was (27±6) %. Twenty-four patients died. The 5-year OS rates of patients with MRD>5% on day 15 of induction therapy was significantly worse than those with MRD≤5% ((60±12) % vs. (72±6) %, χ(2)=3.904, P=0.048) . The 5-year EFS and OS rates were obviously lower in patients with MRD>10% before the consolidation therapy ((50±35) %). The 5-year OS rates of patients with relapsed disease was significantly worse than those without ((26±13) % vs. (81±5) %, χ(2)=18.411, P<0.01). The earlier the relapse, the worse the prognosis. The 5-year OS rates for patients relapsed within 6 months, within 3 years and more than 3 years, were (25±22) %, (30±14) % and (50±35) % respectively (χ(2)=13.207, P<0.01). Conclusions: NPCLC-ALL2008 protocol is effective for childhood T-ALL. The MRD guided accurate risk stratification and individualized treatment can reduce the relapse and improve the survival rate of pediatric T-ALL.

[Clinical and laboratory analysis of 17 patients with γδT-cell large granular lymphocyte leukemia].

Objective: To compare the difference of the clinical and laboratory characteristics between γδ T-cell large granular lymphocyte leukemia (γδT-LGLL) and αß T-cell large granular lymphocyte leukemia (αßT-LGLL) . Methods: The clinical and laboratory characteristics of 17 patients with γδT-LGLL and 91 patients with αßT-LGLL in the department of therapeutic center of anemia of enrolled in our hospital from January 2009 to January 2019 were retrospectively analyzed. Results: The median age of the 17 patients with γδT-LGLL was 54 years (range, 25-73 years) , the most common presenting symptom was anemia. In comparison with αßT-LGLL patients, splenomegaly was common (41% and 44%, respectively) , whereas hepatomegaly (12% and 5%, respectively) and lymphadenopathy (6% and 8%, respectively) were rare. The positive rates of antinuclear antibody (59% and 45%, respectively) were high, whereas the positive rates of rheumatoid factor (6% and 10%, respectively) were rare for both groups. There were no differences on peripheral blood counts between the two groups. However, γδT-LGLL patients were found to be predominantly expressed a CD4(-)/CD8(-) phenotype. Steroid therapy with prednisone was used alone as first-line therapy for 1 patient. Cyclosporin A (CsA) was used alone as first-line therapy for 3 patients. CsA in combination with steroids were administered in 13 patients. After 4 months treatment, 2 patients acquired complete response, 4 patients acquired partial response, the overall response was 35%. Conclusion: γδT-LGLL is a rare mature T-lymphocyte proliferative disease. Clinical and laboratory characteristics were quite similar for γδT-LGLL in compare with αßT-LGLL. γδT-LGLL predominantly expressed a CD4(-)/CD8(-) phenotype. The data presented here indicate the CsA is an effective option for the first-line treatment of γδT-LGLL.

Clinical and laboratory analysis of 17 patients with γδT-cell large granular lymphocyte leukemia / 中华血液学杂志

Objective: To compare the difference of the clinical and laboratory characteristics between γδ T-cell large granular lymphocyte leukemia (γδT-LGLL) and αβ T-cell large granular lymphocyte leukemia (αβT-LGLL) . Methods: The clinical and laboratory characteristics of 17 patients with γδT-LGLL and 91 patients with αβT-LGLL in the department of therapeutic center of anemia of enrolled in our hospital from January 2009 to January 2019 were retrospectively analyzed. Results: The median age of the 17 patients with γδT-LGLL was 54 years (range, 25-73 years) , the most common presenting symptom was anemia. In comparison with αβT-LGLL patients, splenomegaly was common (41% and 44%, respectively) , whereas hepatomegaly (12% and 5%, respectively) and lymphadenopathy (6% and 8%, respectively) were rare. The positive rates of antinuclear antibody (59% and 45%, respectively) were high, whereas the positive rates of rheumatoid factor (6% and 10%, respectively) were rare for both groups. There were no differences on peripheral blood counts between the two groups. However, γδT-LGLL patients were found to be predominantly expressed a CD4(-)/CD8(-) phenotype. Steroid therapy with prednisone was used alone as first-line therapy for 1 patient. Cyclosporin A (CsA) was used alone as first-line therapy for 3 patients. CsA in combination with steroids were administered in 13 patients. After 4 months treatment, 2 patients acquired complete response, 4 patients acquired partial response, the overall response was 35%. Conclusion: γδT-LGLL is a rare mature T-lymphocyte proliferative disease. Clinical and laboratory characteristics were quite similar for γδT-LGLL in compare with αβT-LGLL. γδT-LGLL predominantly expressed a CD4(-)/CD8(-) phenotype. The data presented here indicate the CsA is an effective option for the first-line treatment of γδT-LGLL.

Clinical and laboratory analysis of 17 patients with γδT-cell large granular lymphocyte leukemia / 中华血液学杂志

Objective@#To compare the difference of the clinical and laboratory characteristics between γδ T-cell large granular lymphocyte leukemia (γδT-LGLL) and αβ T-cell large granular lymphocyte leukemia (αβT-LGLL) .@*Methods@#The clinical and laboratory characteristics of 17 patients with γδT-LGLL and 91 patients with αβT-LGLL in the department of therapeutic center of anemia of enrolled in our hospital from January 2009 to January 2019 were retrospectively analyzed.@*Results@#The median age of the 17 patients with γδT-LGLL was 54 years (range, 25-73 years) , the most common presenting symptom was anemia. In comparison with αβT-LGLL patients, splenomegaly was common (41% and 44%, respectively) , whereas hepatomegaly (12% and 5%, respectively) and lymphadenopathy (6% and 8%, respectively) were rare. The positive rates of antinuclear antibody (59% and 45%, respectively) were high, whereas the positive rates of rheumatoid factor (6% and 10%, respectively) were rare for both groups. There were no differences on peripheral blood counts between the two groups. However, γδT-LGLL patients were found to be predominantly expressed a CD4−/CD8− phenotype. Steroid therapy with prednisone was used alone as first-line therapy for 1 patient. Cyclosporin A (CsA) was used alone as first-line therapy for 3 patients. CsA in combination with steroids were administered in 13 patients. After 4 months treatment, 2 patients acquired complete response, 4 patients acquired partial response, the overall response was 35%.@*Conclusion@#γδT-LGLL is a rare mature T-lymphocyte proliferative disease. Clinical and laboratory characteristics were quite similar for γδT-LGLL in compare with αβT-LGLL. γδT-LGLL predominantly expressed a CD4−/CD8− phenotype. The data presented here indicate the CsA is an effective option for the first-line treatment of γδT-LGLL.

[Outcome of 126 adolescent and adult T-cell acute leukemia/lymphoma patients and the prognostic significance of early T-cell precursor leukemia subtype].

Objective: To evaluate the clinical characteristics of T-cell acute leukemia/lymphoma (T-ALL) and explore the prognosis significance of early T-cell precursor leukemia/lymphoma. Methods: A cohort of 126 patients diagnosed with T-ALL from 2008 to 2014 in West China Hospital, Sichuan University were enrolled in this study. They were further categorized by immunophenotype according to the expression of T-cell lineage markers CD1a, CD8, CD5 and one or more stem cell or myeloid markers. The laboratory indicators and prognosis factors were also statistically analyzed. Results: Of all patients, the ratio of male to female was 2.5∶1, with the median age of 25 years old (range 14 to 77) . The percentage of ETP-ALL was up to 47.6%. T-ALL patients showed higher ratio in first clinical remission rate (CR(1)) than T-LBL ones (64.4% vs 30.8%, P=0.032) . Group with WBC count higher than 50×10(9)/L at presentation showed higher ration of achieving CR(1) than those lower than 50×10(9)/L (78.4% vs 50.9%, P=0.010) . In comparison with the non-ETP-ALL, ETP-ALL patients had older age of onset (P<0.001) , lower WBC count (P<0.001) , lower risk of CNS involvement (10.0% vs 30.2%, P=0.009) and slightly inferior overall survival (P=0.073) . T-cell lineage markers CD1a(-), CD8(-) and CD4(-) positive patients had higher CR(1) than their corresponding negative ones (P=0.002, P=0.000, P=0.001) , while CD33(-) and CD56(-) positive patients had lower ratio of achieving CR(1) than their negative ones, respectively (P=0.035, P=0.035) . Conclusion: Flow cytometry and associated markers for immunophenotyping was of significance in the diagnosis and prognosis monitoring of T-ALL/LBL. The percentage of ETP-ALL/LBL subtype was high in Chinese adolescent and adult T-ALL patients. ETP-ALL/LBL was a high risk subtype, which needs more precise standard for diagnosis and advanced therapies for better outcome.

[Primary cutaneous localization revealing leukemia/T-cell lymphoma associated with chronic HTLV-1 infection in a adult. A case presentation]. / Localisation cutanée révélatrice d'une leucémie/lymphome T de l'adulte.

Adult T-cell leukemia/lymphoma (ATLL) is a rare medical condition and a diagnosis that ought to be considered for patients living in an area endemic for the HTLV-1 virus (human T-lymphotrophic virus) where a T-cell lymphoproliferative diagnosis has been made. The cutaneous clinical forms may be the first manifestation of the disease. We report here an observation in a 60-year-old Senegalese woman whose skin lesions were sampled to reveal the ATLL immunophenotypic profile CD4+, CD25+, FoxP3-, and CD7-. HTLV-1 seropositivity confirmed the histopathological diagnosis, and should be corroborated by demonstration of a molecular clonal rearrangement by PCR (Polymerase Chain Reaction). This is a problem because such techniques are not always available in Africa.

Outcome of 126 adolescent and adult T-cell acute leukemia/lymphoma patients and the prognostic significance of early T-cell precursor leukemia subtype / 中华血液学杂志

Objective: To evaluate the clinical characteristics of T-cell acute leukemia/lymphoma (T-ALL) and explore the prognosis significance of early T-cell precursor leukemia/lymphoma. Methods: A cohort of 126 patients diagnosed with T-ALL from 2008 to 2014 in West China Hospital, Sichuan University were enrolled in this study. They were further categorized by immunophenotype according to the expression of T-cell lineage markers CD1a, CD8, CD5 and one or more stem cell or myeloid markers. The laboratory indicators and prognosis factors were also statistically analyzed. Results: Of all patients, the ratio of male to female was 2.5∶1, with the median age of 25 years old (range 14 to 77) . The percentage of ETP-ALL was up to 47.6%. T-ALL patients showed higher ratio in first clinical remission rate (CR(1)) than T-LBL ones (64.4% vs 30.8%, P=0.032) . Group with WBC count higher than 50×10(9)/L at presentation showed higher ration of achieving CR(1) than those lower than 50×10(9)/L (78.4% vs 50.9%, P=0.010) . In comparison with the non-ETP-ALL, ETP-ALL patients had older age of onset (P<0.001) , lower WBC count (P<0.001) , lower risk of CNS involvement (10.0% vs 30.2%, P=0.009) and slightly inferior overall survival (P=0.073) . T-cell lineage markers CD1a(-), CD8(-) and CD4(-) positive patients had higher CR(1) than their corresponding negative ones (P=0.002, P=0.000, P=0.001) , while CD33(-) and CD56(-) positive patients had lower ratio of achieving CR(1) than their negative ones, respectively (P=0.035, P=0.035) . Conclusion: Flow cytometry and associated markers for immunophenotyping was of significance in the diagnosis and prognosis monitoring of T-ALL/LBL. The percentage of ETP-ALL/LBL subtype was high in Chinese adolescent and adult T-ALL patients. ETP-ALL/LBL was a high risk subtype, which needs more precise standard for diagnosis and advanced therapies for better outcome.

Outcome of 126 adolescent and adult T-cell acute leukemia/lymphoma patients and the prognostic significance of early T-cell precursor leukemia subtype / 中华血液学杂志

Objective@#To evaluate the clinical characteristics of T-cell acute leukemia/lymphoma (T-ALL) and explore the prognosis significance of early T-cell precursor leukemia/lymphoma.@*Methods@#A cohort of 126 patients diagnosed with T-ALL from 2008 to 2014 in West China Hospital, Sichuan University were enrolled in this study. They were further categorized by immunophenotype according to the expression of T-cell lineage markers CD1a, CD8, CD5 and one or more stem cell or myeloid markers. The laboratory indicators and prognosis factors were also statistically analyzed.@*Results@#Of all patients, the ratio of male to female was 2.5∶1, with the median age of 25 years old (range 14 to 77) . The percentage of ETP-ALL was up to 47.6%. T-ALL patients showed higher ratio in first clinical remission rate (CR1) than T-LBL ones (64.4% vs 30.8%, P=0.032) . Group with WBC count higher than 50×109/L at presentation showed higher ration of achieving CR1 than those lower than 50×109/L (78.4% vs 50.9%, P=0.010) . In comparison with the non-ETP-ALL, ETP-ALL patients had older age of onset (P<0.001) , lower WBC count (P<0.001) , lower risk of CNS involvement (10.0% vs 30.2%, P=0.009) and slightly inferior overall survival (P=0.073) . T-cell lineage markers CD1a-, CD8- and CD4- positive patients had higher CR1 than their corresponding negative ones (P=0.002, P=0.000, P=0.001) , while CD33- and CD56- positive patients had lower ratio of achieving CR1 than their negative ones, respectively (P=0.035, P=0.035) .@*Conclusion@#Flow cytometry and associated markers for immunophenotyping was of significance in the diagnosis and prognosis monitoring of T-ALL/LBL. The percentage of ETP-ALL/LBL subtype was high in Chinese adolescent and adult T-ALL patients. ETP-ALL/LBL was a high risk subtype, which needs more precise standard for diagnosis and advanced therapies for better outcome.

Approaches for generation of anti-leukemia specific T cells.

As three decades ago, it was reported that adoptive T cell immunotherapy by infusion of autologous tumor infiltrating lymphocytes (TILs) mediated objective cancer regression in patients with metastatic melanoma. A new era of T cell immunotherapy arose since the improvement and clinical use of anti-CD19 chimeric antigen receptor T cells (CAR-T) for the treatment of refractory and relapsed B lymphocyte leukemia. However, several challenges and difficulties remain on the way to reach generic and effective T cell immunotherapy, including lacking a generic method for generating anti-leukemia-specific T cells from every patient. Here, we summarize the current methods of generating anti-leukemia-specific T cells, and the promising approaches in the future.

Characteristics and clinical significance of phosphatase and tensin homolog mutations in adult T-cell acute lymphoblastic leukemia / 白血病·淋巴瘤

Objective@#To detect the characteristics of phosphatase and tensin homolog (PTEN) mutations in adult T-cell acute lymphoblastic leukemia (T-ALL) and its relationship with the prognosis.@*Methods@#Fifty-five adult T-ALL patients were enrolled in Jiangsu Province Hospital from February 2010 to April 2016. Mononuclear bone marrow cells were extracted by using Ficoll density gradient centrifugation. Genomic DNA was extracted from isolated mononuclear cells. Amplified exon 1-9 of PTEN by polymerase chain reaction (PCR) specifically amplified PTEN exon, then DNA was purified, sequenced and compared. The mutation occurrence rate, mutation types, and the relations with several clinical indicators were analyzed.@*Results@#PTEN mutations were detected in 5 patients, and 8 types of mutations were detected in 55 T-ALL patients with mutation rate of 9.1% (5/55). All the mutations were located in exon 7 of the genes. Five patients with PTEN mutations also merged other gene mutations like NOTCH1 and DNM2. The level of median lactate dehydrogenase (LDH) in patients with PTEN mutations was higher than that in patients without PTEN mutations (3 358 U/L vs. 755 U/L, Z=-2.014, P= 0.044). No significant differences were found in gender, age, white blood count, hemoglobin, platelet count, overall survival rate, event free survival, recurrence free survival between the two groups (P > 0.05).@*Conclusion@#PTEN is a tumor suppressor gene, and its mutation plays a significant role in the occurrence and development of adult T-ALL patients, which may be associated with the poor prognosis.

[HSP90 inhibitor 17-AAG plays an important role in JAK3/STAT5 signaling pathways in HTLV-1 infection cell line HUT-102].

Objective: To analyze whether heat-shock protein 90 (HSP90) be involved in a permanently abnormal activated JAK/STAT signaling in ATL cells in vitro. Methods: The effect of 17-AAG on proliferation of ATL cell lines HUT-102 was assessed using CCK8 at different time points. Cell apoptosis was measured by flow cytometry. The specific proteins HSP90, STAT5, p-STAT5 and JAK3 were detected by Western blotting. Results: Overexpression of HSP90 in HUT-102 cell lines was disclosed (P<0.05) , and constitutive activation of JAK3/STAT5 signaling was observed in HTLV-1-infected T-cell lines but not in normal PBMCs; Treatment of ATL cell lines with 17-AAG led to reduced cell proliferation, but there was no significant change in terms of cell proliferation when the concentration of 17-AAG between 2 000-8 000 nmol/L (P>0.05) . 17-AAG induced cell apoptosis in different time-points and concentrations. 17-AAG don't affect the expression of JAK3 gene. Conclusion: This study indicated that JAK3 as HSP90 client protein was aberrantly activated in HTLV-1-infected T-cell lines, leading to constitutive activation of p-STAT5 in JAK/STAT signal pathway, which demonstrated that HSP90-inhibitors 17-AAG inhibited the growth of HTLV-1-infected T-cell lines by reducing cell proliferation and inducing cell apoptosis.

HSP90 inhibitor 17-AAG plays an important role in JAK3/STAT5 signaling pathways in HTLV-1 infection cell line HUT-102 / 中华血液学杂志

Objective@#To analyze whether heat-shock protein 90 (HSP90) be involved in a permanently abnormal activated JAK/STAT signaling in ATL cells in vitro.@*Methods@#The effect of 17-AAG on proliferation of ATL cell lines HUT-102 was assessed using CCK8 at different time points. Cell apoptosis was measured by flow cytometry. The specific proteins HSP90, STAT5, p-STAT5 and JAK3 were detected by Western blotting.@*Results@#Overexpression of HSP90 in HUT-102 cell lines was disclosed (P<0.05) , and constitutive activation of JAK3/STAT5 signaling was observed in HTLV-1-infected T-cell lines but not in normal PBMCs; Treatment of ATL cell lines with 17-AAG led to reduced cell proliferation, but there was no significant change in terms of cell proliferation when the concentration of 17-AAG between 2 000-8 000 nmol/L (P>0.05) . 17-AAG induced cell apoptosis in different time-points and concentrations. 17-AAG don’t affect the expression of JAK3 gene.@*Conclusion@#This study indicated that JAK3 as HSP90 client protein was aberrantly activated in HTLV-1-infected T-cell lines, leading to constitutive activation of p-STAT5 in JAK/STAT signal pathway, which demonstrated that HSP90-inhibitors 17-AAG inhibited the growth of HTLV-1-infected T-cell lines by reducing cell proliferation and inducing cell apoptosis.

Philadelphia chromosome positive pre-T cell acute lymphoblastic leukemia: a rare case report and short review.

Pre-T cell acute lymphoblastic leukemia is a relatively rare leukemia. Twenty to 30 % of adult B cell leukemia cases are Philadelphia chromosome positive and it has a therapeutic and prognostic significance. Incidence and outcome of Ph+ T cell acute lymphoblastic leukemia (T cell ALL) is unknown. Only about 25 cases of de novo Ph+ T cell ALL and 44 cases of Ph+ T ALL in blastic phase of CML has been reported. Differentiation between Ph+ Pre-T ALL/LBL and T cell lymphoblastic crises of chronic myeloid leukemia may be difficult. We report a case of adult T cell ALL having Philadelphia chromosome as the cytogenetic abnormality. He was treated with acute lymphoblastic leukemia induction chemotherapy and Imatinib and achieved complete remission.

T-cell prolymphocytic leukemia with extensive cardiovascular infiltrate leading to multiple myocardial infarctions and cardiac death.

Lymphocytic neoplasm involving the heart is not common and usually presents with pericardial effusion or focal myocardial infiltration. Myocardial infarctions due to leukemic infiltration of the coronary arteries are rarely reported. We present the case of a 52-year-old Guatemalan man with a one-year history of untreated T-cell prolymphocytic leukemia. He was admitted to our hospital for chemotherapy and evaluation of a pulmonary cavitary lesion by wedge resection. During sedation, the patient experienced acute respiratory failure and hypovolemic shock, from which he could not be resuscitated. Autopsy revealed that leukemic cells extensively infiltrated the aorta, myocardium, and coronary arteries. The lumina of the 3 major coronary artery branches showed 70% to 95% stenosis, with multifocal remote myocardial infarctions. Tumor cells were also detected in the lungs and other organs. The acute cardiorespiratory insufficiency secondary to leukemia-particularly the extensive infiltration of the coronary arteries and myocardium, and the multiple myocardial infarctions-eventually resulted in cardiac death.

Leucemia/linfoma T del adulto en pacientes infectados con HTLV-1: reporte de dos casos de Colombia / Adult T-cell leukemia/lymphoma in HTLV-1 infected patients: report of two cases in Colombia

La leucemia/linfoma de células T del adulto ( Adult T-Cell Leukemia/Lymphoma , ATLL) es una neoplasia maligna de los linfocitos T CD4 maduros, que resulta de la infección con el virus T-linfotrópico humano de tipo 1 (HTLV-1), con varias manifestaciones sistémicas y cutáneas. Se presentan dos casos de leucemia/linfoma de células T del adulto en pacientes del suroccidente de Colombia, cuyos diagnósticos fueron confirmados por histología, inmunohistoquímica, citometría de flujo y pruebas ELISA y Western blot. También, se discute acerca del virus y cómo hacer el diagnóstico en países como el nuestro.

Adult T-cell leukemia/lymphoma (ATLL) is a malignant neoplasia of mature CD4+ T lymphocytes,resulting from infection with human T-lymphotropic virus type 1 (HTLV-1), with several systemic and cutaneous manifestations. We present two cases of adult T-cell leukemia/lymphoma, in patients from the Colombian Southwestern region, whose diagnoses were confirmed by histology, immunohistochemistry, flow cytometry, ELISA and Western blot tests. We also discuss about the virus and how to make this diagnosis in countries like Colombia.

Progress on Notch signaling in T-cell acute lymphoblastic leukemia / 白血病·淋巴瘤

T-cell acute lymphoblastic leukemia (T-ALL) is one of the most common types of leukemia in children. With over 50 ％ of activating Notch1mutations in T-ALL,identification of activating Notch1mutations has brought interest toward targeting the Notch signaling pathway in this disease.Small-molecule γ-secretase inhibitors (GSI) can block a critical proteolytic step required for Notch1activation,but the clinical application of GSI has been hindered. Therefore, new therapeutic strategies aim to design of effective antiNotch1therapies in T-ALL are needed, including combination therapies with molecularly targeted drugs and glucocorticoids. This review put emphasis on the molecular basis of Notch1, the mechanisms of action of oncogenic Notch1and clinical significance of Notch 1mutations in T-ALL.

Research progress on relationship between Notch signaling and hematological disorders / 白血病·淋巴瘤

Notch signaling can control T cell development and differentiation and lead to acute T cell lymphoma/leukemia (T-ALL). Most Notch1mutations in human T-ALL are the HD domain and the PEST domain. Aberrant Notch1activation can induce T-ALL by PI3K/Akt, mTOR or/and NF-κB pathways. Some recent reports suggested that Notch signaling could not only control T cell development,but also has a role in acute myeloid leukemia (AML) and Graft-versus-host Disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT).Moreover,Notch signaling can regulate the expansion of HSC as well as generate increased numbers of progenitor cells which are capable of rapid repopulation to improve HSC homeostasis and hematopoietic recovery after allo-HSCT.

Expression of FBXW7 in a murine model of T-cell acute lymphoblastic leukemia / 白血病·淋巴瘤

Objective To investigate the expression of FBXW7 during the development of Notch1induced murine leukemia.Methods Notch1 over-expressing murine model of T-cell acute lymphoblastic leukemia was used to study the expression of FBXW7 by real-time PCR methods.Bone marrow mononuclear cells (BMNC) were isolated on different days after transplantation and CD45.2+ GFP+ leukemia cells were sorted by flow cytometry at late stage.The expression changes of FBXW7 were tested by real-time PCR.Results The mouse bone marrow cells both from leukemia and control groups expressed FBXW7.Different expression patterns of FBXW7 were observed during the development of leukemia. The expression of FBXW7 was gradually increased in control group, whereas the expression level of FBXW7 in leukemia group was decreased steadily and reached one-sixth of that in control group on 12th day.Furthermore,lower expression level of FBXW7 was observed in CD45+.2 GFP+ leukemia cells.Conclusion Decreased expression of FBXW7 is observed in Notch1-induced mouse leukemia model,suggesting that the abnormal ubiquitin degradation pathway mediated by FBXW7 might contribute to the leukemogenesis in Notch1-induced murine leukemia model.