- A Phase I Dose-Escalation Study of Clofarabine in Patients with Relapsed or Refractory Low-Grade or Intermediate-Grade B-Cell or T-Cell Lymphoma. [Journal Article]
- OOncologist 2018 Feb 07
- CONCLUSIONS: Clofarabine can be active in relapsed and refractory lymphoid malignancies on a weekly dosing schedule.Responses were seen in patients with T-cell lymphomas, including cutaneous T-cell lymphoma, but not in patients with aggressive B-cell lymphomas.In this study, weekly administration of clofarabine was demonstrated to be safe and associated with minimal hematologic toxicity at doses ranging from 10-40 mg/m2. In prior studies when dosed daily for 5 consecutive days, the MTD was shown to be 4 mg/m2. Weekly dosing within this dose range did not result in dose modifications, and the MTD was not reached. Clinical efficacy was observed in one patient with CTCL who was treated in the lowest-dose cohort.
- Transformation of Chronic Lymphocytic Leukemia (CLL) into B-cell Acute Lymphoblastic Leukemia (ALL). [Journal Article]
- BloodBlood 2018 Feb 05
- MicroRNA expression and activity in T-cell acute lymphoblastic leukemia. [Review]
- OOncotarget 2018 Jan 12; 9(4):5445-5458
- T-cell acute lymphoblastic leukemia (T-ALL) is a lymphoid malignancy caused by the oncogenic transformation of immature T-cell progenitors. Many biologically relevant genetic and epigenetic alteratio...
T-cell acute lymphoblastic leukemia (T-ALL) is a lymphoid malignancy caused by the oncogenic transformation of immature T-cell progenitors. Many biologically relevant genetic and epigenetic alterations have been identified as driving factors for this transformation. Recently, microRNAs (miRNAs) have been shown to influence various leukemias, including T-ALL. Aberrant expression of miRNAs can function as either oncogenes or tumor suppressors in T-ALL through the regulation of cell migration, invasion, proliferation, apoptosis, and chemoresistance. This occurs by targeting key signaling pathways or transcriptional factors that play a critical role in T-ALL pathology and progression. Different miRNA expression profiles have been linked to specific genetic subtypes of human T-ALL. Furthermore, miRNAs can also act as independent prognostic factors to predict clinical outcomes for T-ALL patients. In the current review, we will focus on the role of miRNAs in the development and progression of T-ALL.
- A unique bone marrow lymphoma patient presenting with an isolated mass: A case report. [Journal Article]
- OLOncol Lett 2018; 15(2):2529-2533
- Bone marrow lymphoma with the onset of an isolated mass in the bone marrow is extremely rare. The present case report described a unique case of B cell lymphoblastic lymphoma (LBL) presenting with an...
Bone marrow lymphoma with the onset of an isolated mass in the bone marrow is extremely rare. The present case report described a unique case of B cell lymphoblastic lymphoma (LBL) presenting with an isolated mass in the bone marrow cavity, without any organopathy or lymphadenopathy. An isolated mass in bone marrow is a rare primary manifestation of LBL. The patient in the present case report presented with pain in the right elbow, a fever, pancytopenia and splenomegaly. Additionally, no abnormality was determined in the lymph nodes, the bone marrow karyotype or a computed tomography scan of the humerus. Positron emission tomography (PET) examination revealed an increased uptake of 18F-fluorodeoxyglucose in right distal humerus. An isolated mass in the bone marrow cavity was removed by surgery. Pathological findings revealed B cell LBL. The patient received an acute lymphocytic leukemia chemotherapy regimen and achieved complete remission. However, 4 months following the initial diagnosis, the patient succumbed due to a relapse. The present case highlighted the importance of PET examination and biopsy, and the requirement to identify appropriate treatments for LBL. Additionally, it is important to broaden the differential diagnosis when an isolated mass is identified in the bone marrow cavity.
- Application of GATA-3 gene marker in the detection of hematologic disorders in children. [Journal Article]
- ETExp Ther Med 2018; 15(2):1879-1885
- The aim of the present study was to investigate the use of GATA-3 markers in the detection of hematologic disorders in children. In total, 35 pediatric patients diagnosed with blood disease and treat...
The aim of the present study was to investigate the use of GATA-3 markers in the detection of hematologic disorders in children. In total, 35 pediatric patients diagnosed with blood disease and treated in Henan Red Cross Blood Center from January 2014 to June 2015 were selected for the observation group. Another 32 healthy children were selected for the control group. The differences in the GATA-3 mRNA expression levels between the control and observation groups were detected via reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The differences in the GATA-3 protein expression levels were detected via enzyme-linked immunosorbent assay (ELISA) and western blot analysis. Compared with those in the healthy children, the mRNA expression levels of GATA-3 in patients with hematologic malignancies, acute lymphoblastic leukemia, myeloproliferative disorder, acute non-lymphocytic leukemia or thrombocytopenic purpura were significantly higher, and there were statistically significant differences between the groups (P<0.05). The results of ELISA showed that the GATA-3 protein expression levels in patients with hematologic malignancies (241.3±42.6 µg/l), acute lymphoblastic leukemia (196.3±21.6 µg/l), myeloproliferative disorder (284.2±45.1 µg/l), acute non-lymphocytic leukemia (269.3±31.4 µg/l) or thrombocytopenic purpura (272.1±39.1 µg/l) were significantly higher than those in healthy subjects (69.3±15.2 µg/l). The results of western blot analysis were consistent with those of ELISA. Based on our results, the expression levels of GATA-3 in healthy children and pediatric patients with blood diseases exhibit significant differences, and can be used as important markers for the clinical diagnosis of blood diseases in children.
- Reprint of: Building a Safer and Faster CAR: Seatbelts, Airbags, and CRISPR. [Review]
- BBBiol Blood Marrow Transplant 2018; 24(3S):S15-S19
- Therapeutic T cell engineering has recently garnered widespread interest because of the success of CD19 chimeric antigen receptor (CAR) therapy. CARs are synthetic receptors for antigen that redirect...
Therapeutic T cell engineering has recently garnered widespread interest because of the success of CD19 chimeric antigen receptor (CAR) therapy. CARs are synthetic receptors for antigen that redirect the specificity and reprogram the function of the T cells in which they are genetically introduced. CARs targeting CD19, a cell surface molecule found in most leukemias and lymphomas, have yielded high remission rates in patients with chemorefractory, relapsed disease, including acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma. The toxicities of this treatment include B cell aplasia, cytokine release syndrome (CRS), and neurotoxicity. Although reversible in most instances, these toxicities may require specific medical interventions, including transfer to intensive care to treat severe CRS. Guidelines for managing these toxicities are emerging. The recent report of a nonhuman primate model for CRS is poised to help advance the management of this syndrome. Finally, new engineering modalities, based on the use of targeted nucleases like CRISPR, may further enhance the efficacy and safety of CAR T cells.
- Identification of survivin as a promising target for the immunotherapy of adult B-cell acute lymphoblastic leukemia. [Journal Article]
- OOncotarget 2018 Jan 09; 9(3):3853-3866
- B-cell acute lymphoblastic leukemia (B-ALL) is a rare heterogeneous disease characterized by a block in lymphoid differentiation and a rapid clonal expansion of immature, non-functioning B cells. Adu...
B-cell acute lymphoblastic leukemia (B-ALL) is a rare heterogeneous disease characterized by a block in lymphoid differentiation and a rapid clonal expansion of immature, non-functioning B cells. Adult B-ALL patients have a poor prognosis with less than 50% chance of survival after five years and a high relapse rate after allogeneic haematopoietic stem cell transplantation. Novel treatment approaches are required to improve the outcome for patients and the identification of B-ALL specific antigens are essential for the development of targeted immunotherapeutic treatments. We examined twelve potential target antigens for the immunotherapy of adult B-ALL. RT-PCR indicated that only survivin and WT1 were expressed in B-ALL patient samples (7/11 and 6/11, respectively) but not normal donor control samples (0/8). Real-time quantitative (RQ)-PCR showed that survivin was the only antigen whose transcript exhibited significantly higher expression in the B-ALL samples (n = 10) compared with healthy controls (n = 4)(p = 0.015). Immunolabelling detected SSX2, SSX2IP, survivin and WT1 protein expression in all ten B-ALL samples examined, but survivin was not detectable in healthy volunteer samples. To determine whether these findings were supported by the analyses of a larger cohort of patient samples, we performed metadata analysis on an already published microarray dataset. We found that only survivin was significantly over-expressed in B-ALL patients (n = 215) compared to healthy B-cell controls (n = 12)(p = 0.013). We have shown that survivin is frequently transcribed and translated in adult B-ALL, but not healthy donor samples, suggesting this may be a promising target patient group for survivin-mediated immunotherapy.
- Cathepsin G Is Expressed by Acute Lymphoblastic Leukemia and Is a Potential Immunotherapeutic Target. [Journal Article]
- FIFront Immunol 2017; 8:1975
- Cathepsin G (CG) is a myeloid azurophil granule protease that is highly expressed by acute myeloid leukemia (AML) blasts and leukemia stem cells. We previously identified CG1 (FLLPTGAEA), a human leu...
Cathepsin G (CG) is a myeloid azurophil granule protease that is highly expressed by acute myeloid leukemia (AML) blasts and leukemia stem cells. We previously identified CG1 (FLLPTGAEA), a human leukocyte antigen-A2-restricted nonameric peptide derived from CG, as an immunogenic target in AML. In this report, we aimed to assess the level of CG expression in acute lymphoid leukemia (ALL) and its potential as an immunotherapeutic target in ALL. Using RT-PCR and western blots, we identified CG mRNA and protein, respectively, in B-ALL patient samples and cell lines. We also examined CG expression in a large cohort of 130 patients with ALL via reverse-phase protein array (RPPA). Our data show that CG is widely expressed by ALL and is a poor prognosticator. In addition to endogenous expression, we also provide evidence that CG can be taken up by ALL cells. Finally, we demonstrate that patient ALL can be lysed by CG1-specific cytotoxic T lymphocytes in vitro. Together, these data show high expression of CG by ALL and implicate CG as a target for immunotherapy in ALL.
- HPRT1 activity loss is associated with resistance to thiopurine in ALL. [Journal Article]
- OOncotarget 2018 Jan 05; 9(2):2268-2278
- Acute lymphoblastic leukemia (ALL) is an aggressive hematological tumor resulting from the malignant transformation of lymphoid progenitors. Thiopurine is a widely used drug in the maintaining treatm...
Acute lymphoblastic leukemia (ALL) is an aggressive hematological tumor resulting from the malignant transformation of lymphoid progenitors. Thiopurine is a widely used drug in the maintaining treatment of ALL. After a period of chemotherapy, 20% of pediatric patients and over 50% of adult patients will relapse. To investigate the mechanisms of drug resistance in vitro, we established the thiopurine resistant cell lines Reh-6MPR (6-MP Resistant cell) and Reh-6TGR (6-TG Resistant cell) by stepwise selection of the ALL cell line Reh. Cell viability assay revealed that 6MPR and 6TGR cells were almost 1000-fold more resistant to thiopurine comparing with the control Reh cells, and thiopurine conversion was significantly impaired in the resistant cells. Mechanistically, a same novel hypoxanthine phosphoribosyl transferase 1 (HPRT1) mutation c.495_496insA (p.V165fs) was found by whole exome sequencing in both resistant cells. The HPRT1 mutation dramaticly decreased the production of [13C5,15N4]-IMP from [13C5,15N4]-hypoxanthine (HX), showed a loss-of-funciton mechanism. Notably, re-expression the wildtype HPRT1 in Reh-6MPR cell can reverse the drug resistance and thiopurine conversion in Reh-6MPR cells. These results highlight the importance of HPRT1's activity in thiopurine resistance.
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- Incidence of acute lymphocytic leukemia in Calgary, Alberta, Canada: a retrospective cohort study. [Journal Article]
- BRBMC Res Notes 2018 Feb 07; 11(1):104
- Acute lymphocytic leukemia (ALL) is a rare malignant neoplasm that develops from abnormal lymphoid stem cells. ALL incidence is highest among children and declines towards adolescence. There is limit...
Acute lymphocytic leukemia (ALL) is a rare malignant neoplasm that develops from abnormal lymphoid stem cells. ALL incidence is highest among children and declines towards adolescence. There is limited data on the epidemiology of ALL, especially in Canada. This retrospective cohort study used patient data from the Calgary Laboratory Services Cancer Cytogenetics Laboratory to report the incidence rate of ALL in Calgary, Alberta, Canada. New cases of ALL were identified for the 5-year period of January 1, 2011 until December 31, 2015. Reported incidence rates were categorized by sex and age groups, and age-standardized to the Canadian population.