Biological and clinical significance of in vitro prednisolone resistance in adult acute lymphoblastic leukaemia

2009 ◽  
Vol 57 (2) ◽  
pp. 134-141 ◽  
Author(s):  
P. Tosi ◽  
G. Visani ◽  
E. Ottaviani ◽  
S. Manfroi ◽  
S. Tura
Keyword(s):  
Acute Lymphoblastic Leukaemia ◽  
Clinical Significance ◽  
Lymphoblastic Leukaemia

scholarly journals Bloodstream infection caused by Acinetobacter junii in a patient with acute lymphoblastic leukaemia after allogenic haematopoietic cell transplantation

2011 ◽  
Vol 60 (3) ◽  
pp. 375-377 ◽  
Author(s):  
Rodrigo Cayô ◽  
Lucrecia Yañez San Segundo ◽  
Inmaculada Concepción Pérez del Molino Bernal ◽  
Celia García de la Fuente ◽  
Maria Aranzazu Bermúdez Rodríguez ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukaemia ◽  
Bloodstream Infection ◽  
Clinical Significance ◽  
Lymphoblastic Leukaemia ◽  
Transplant Patient ◽  
Paediatric Oncology ◽  
Correct Identification ◽  
Human Pathogen ◽  
Acinetobacter Junii ◽  
Haematopoietic Cell

Acinetobacter junii is a rare human pathogen associated with bacteraemia in neonates and paediatric oncology patients. We present a case of A. junii causing bacteraemia in an adult transplant patient with leukaemia. The correct identification of Acinetobacter species can highlight the clinical significance of the different species of this genus.

scholarly journals Clinical significance of recurrent copy number aberrations in B-lineage acute lymphoblastic leukaemia without recurrent fusion genes across age cohorts

2017 ◽  
Vol 178 (4) ◽  
pp. 583-587 ◽  
Author(s):  
Monica Messina ◽  
Sabina Chiaretti ◽  
Anna Lucia Fedullo ◽  
Alfonso Piciocchi ◽  
Maria Cristina Puzzolo ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukaemia ◽  
Clinical Significance ◽  
Lymphoblastic Leukaemia ◽  
Copy Number ◽  
Fusion Genes ◽  
Age Cohorts ◽  
Copy Number Aberrations ◽  
B Lineage

Investigating the Expression of the MRD Marker CD58 on Leukaemia Initiating Cells in Childhood Acute Lymphoblastic Leukaemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1887-1887 ◽  
Author(s):  
Charlotte Victoria Cox ◽  
Paraskevi Diamanti ◽  
Allison Blair
Keyword(s):  
Acute Lymphoblastic Leukaemia ◽  
Lymphoblastic Leukaemia ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Model Systems ◽  
Childhood All ◽  
Therapy Assessment ◽  
Childhood Acute Lymphoblastic Leukaemia

Abstract Abstract 1887 Further improvements in outcome for childhood acute lymphoblastic leukaemia (ALL) will require a better understanding of the underlying biology of this disease and the fundamental mechanisms of drug resistance. The discoveries that a few populations can initiate leukemia in mouse models and that new populations of leukaemia initiating cells (LIC) can be detected following an initial round of transplantation in these models raises important questions about the biology of the leukaemias. If several cell populations have LIC properties, what are the relationships of these populations to each other and which populations are most important to target with therapy? It will also be important to determine whether there is any correlation in the biological properties of LIC identified in the model systems with the response of the patients to therapy. Assessment of minimal residual disease (MRD) levels provides a sensitive measurement of early treatment response and permits detection of the in vivo selected drug resistant population. CD58 (leucocyte function-associated antigen 3; LFA-3) is a useful marker in MRD tracking of B cell precursor (BCP) ALL. CD58 is over expressed in these cases permitting discrimination of leukaemia blasts from normal B cells. In this study we investigated whether CD58 is expressed on LIC populations in childhood ALL. Expression of CD58 and CD34 was assessed in a cohort of 12 diagnostic samples with mixed prognoses and compared to levels detected in 11 normal bone marrow (NBM) samples. Levels of CD58 were significantly higher in the ALL cases (57.4±37.7%) than on NBM cells (21.1±12.2%; p=0.007). Likewise, the CD34+/CD58+ population was larger in ALL cases than in normal cells (22.2±34.7% and 0.25±0.25%, respectively; p=0.05). Cells from eight of the 12 patients, were sorted on the basis of expression or lack of expression of these markers and the functional ability of the sorted subpopulations was assessed in vitro and in vivo. On sorting, the majority of cells were CD34−/CD58− (43.7±39.2%), 20.7±30.7% were CD34−/CD58+, 19±14.3% were CD34+/CD58+ and the CD34+/CD58− population accounted for 16.6±35.3%. Unsorted cells and all 4 sorted populations were set up in long-term culture to assess proliferative capability and the in vivo propagating potential was assessed in NSG mice. All 4 sorted subpopulations proliferated over the 6 week period but the highest levels of expansion were observed in the cultures of CD34+/CD58+ (6–420 fold) and CD34+/CD58− (3–24 fold) cells. Cytogenetic analyses confirmed that leukaemia cells were maintained in the culture system. Results from the in vivo analyses on 5 cases to date indicate that all 4 subpopulations contain LIC. In these cases, higher levels of engraftment were observed with CD34+/CD58+ (up to 20%) and with CD34−/CD58− subpopulations (6.1-98%). Serial transplantation studies will determine whether there are differences in the repopulating and self-renewal abilities of these LIC. These findings suggest that using CD58 alone or in combination with CD34 would be insufficient to track disease progression in ALL. Incorporating additional markers that are commonly used in MRD panels will provide valuable information on LIC populations and facilitate development of improved disease monitoring. Disclosures: No relevant conflicts of interest to declare.

scholarly journals In vitro drug resistance and prognostic impact of p16INK4A /P15INK4B deletions in childhood T-cell acute lymphoblastic leukaemia

2001 ◽  
Vol 112 (3) ◽  
pp. 680-690 ◽  
Author(s):  
N. L. Ramakers-van Woerden ◽  
R. Pieters ◽  
R. M. Slater ◽  
A. H. Loonen ◽  
H. B. Beverloo ◽  
...  
Keyword(s):  
Drug Resistance ◽  
T Cell ◽  
Acute Lymphoblastic Leukaemia ◽  
Lymphoblastic Leukaemia ◽  
Prognostic Impact

scholarly journals TYK2 Variants in B-Acute Lymphoblastic Leukaemia

Genes ◽  
2020 ◽  
Vol 11 (12) ◽  
pp. 1434
Author(s):  
Edgar Turrubiartes-Martínez ◽  
Irene Bodega-Mayor ◽  
Pablo Delgado-Wicke ◽  
Francisca Molina-Jiménez ◽  
Diana Casique-Aguirre ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukaemia ◽  
Lymphoblastic Leukaemia ◽  
Target Genes ◽  
Rare Variants ◽  
Novel Mutation ◽  
Janus Kinase ◽  
Dynamics Simulation ◽  
Expression Vectors ◽  
Tyrosine Kinase 2

B-cell precursor acute lymphoblastic leukaemia (B-ALL) is a malignancy of lymphoid progenitor cells with altered genes including the Janus kinase (JAK) gene family. Among them, tyrosine kinase 2 (TYK2) is involved in signal transduction of cytokines such as interferon (IFN) α/β through IFN−α/β receptor alpha chain (IFNAR1). To search for disease-associated TYK2 variants, bone marrow samples from 62 B-ALL patients at diagnosis were analysed by next-generation sequencing. TYK2 variants were found in 16 patients (25.8%): one patient had a novel mutation at the four-point-one, ezrin, radixin, moesin (FERM) domain (S431G) and two patients had the rare variants rs150601734 or rs55882956 (R425H or R832W). To functionally characterise them, they were generated by direct mutagenesis, cloned in expression vectors, and transfected in TYK2-deficient cells. Under high-IFNα doses, the three variants were competent to phosphorylate STAT1/2. While R425H and R832W induced STAT1/2-target genes measured by qPCR, S431G behaved as the kinase-dead form of the protein. None of these variants phosphorylated STAT3 in in vitro kinase assays. Molecular dynamics simulation showed that TYK2/IFNAR1 interaction is not affected by these variants. Finally, qPCR analysis revealed diminished expression of TYK2 in B-ALL patients at diagnosis compared to that in healthy donors, further stressing the tumour immune surveillance role of TYK2.

scholarly journals Targeting aurora kinases as a potential prognostic and therapeutical biomarkers in pediatric acute lymphoblastic leukaemia

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Caroline Aquino Moreira-Nunes ◽  
Felipe Pantoja Mesquita ◽  
Adrhyann Jullyanne de Sousa Portilho ◽  
Fernando Augusto Rodrigues Mello Júnior ◽  
Jersey Heitor da Silva Maués ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukaemia ◽  
Lymphoblastic Leukaemia ◽  
White Blood Cells ◽  
Survival Rates ◽  
Leukemia Cell ◽  
Leukemia Cell Line ◽  
Novel Therapy ◽  
Aurora Kinases ◽  
Mitotic Kinases

AbstractAurora kinases (AURKA and AURKB) are mitotic kinases with an important role in the regulation of several mitotic events, and in hematological malignancies, AURKA and AURKB hyperexpression are found in patients with cytogenetic abnormalities presenting a unfavorable prognosis. The aim of this study was evaluated the mRNA expression profile of pediatric Acute Lymphoblastic Leukaemia (ALL) patients and the efficacy of two AURKA and AURKB designed inhibitors (GW809897X and GW806742X) in a leukemia cell line as a potential novel therapy for ALL patients. Cellular experiments demonstrated that both inhibitors induced cell death with caspase activation and cell cycle arrest, however only the GW806742X inhibitor decreased with more efficacy AURKA and AURKB expression in K-562 leukemia cells. In ALL patients both AURKA and AURKB showed a significant overexpression, when compared to health controls. Moreover, AURKB expression level was significant higher than AURKA in patients, and predicted a poorer prognosis with significantly lower survival rates. No differences were found in AURKA and AURKB expression between gene fusions, immunophenotypic groups, white blood cells count, gender or age. In summary, the results in this study indicates that the AURKA and AURKB overexpression are important findings in pediatric ALL, and designed inhibitor, GW806742X tested in vitro were able to effectively inhibit the gene expression of both aurora kinases and induce apoptosis in K-562 cells, however our data clearly shown that AURKB proves to be a singular finding and potential prognostic biomarker that may be used as a promising therapeutic target to those patients.

Effect of Parthenolide on Stem Cells in Childhood Acute Lymphoblastic Leukaemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1341-1341
Author(s):  
Paraskevi Diamanti ◽  
Charlotte V Cox ◽  
Allison Blair
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Acute Lymphoblastic Leukaemia ◽  
Lymphoblastic Leukaemia ◽  
Therapeutic Agents ◽  
Stem Cell Population ◽  
Normal Peripheral Blood ◽  
Childhood Acute Lymphoblastic Leukaemia ◽  
Short Term Exposure

Abstract Current therapies for the treatment of childhood acute lymphoblastic leukaemia (ALL) have resulted in vastly improved survival rates of around 80% in recent years. Despite these successes, around 15% of patients die of the disease and relapse is the most common cause of treatment failure. Intensification of treatment to prevent or treat relapse may not be a feasible approach due to an increased risk of significant adverse effects. It is possible that ALL may be maintained by a subpopulation of stem cells that are resistant to regimens designed to kill the bulk population and subsequent relapses may arise from these stem cells. Consequently, there is a need to assess the efficacy of therapeutic agents on ALL stem cells. We have previously shown that ALL cells that are capable of initiating and sustaining the disease in serial xenografts have a CD34+/CD19− phenotype. Furthermore, these putative ALL stem cells were resistant to treatment in vitro with dexamethasone and vincristine, two agents routinely used in the treatment of paediatric leukaemia. In this investigation we have examined the effects of the sesquiterpene lactone parthenolide (PTL), a natural compound which induces oxidative stress and inhibits NF-kB. PTL effectively eradicates stem cells in AML and B-CLL in vitro while sparing normal heamopoietic cells. Unsorted leukaemia cells from 11 cases, with mixed prognostic subgroups, were co-cultured with and without PTL at a range of 0–10μM for 18–24 hours. Cell viability and apoptosis were evaluated by flow cytometry using annexin V and propidium iodide staining. Four out of the 11 cases were relatively resistant to treatment with PTL with only small reductions in viability (<5%) and no significant effect on apoptosis, even at the highest dose evaluated. There was no correlation between the prognostic risk group and the response to PTL. Primary cells from the 4 resistant cases were sorted into CD34+/CD19+ and CD34+/CD19− subfractions to assess the effect of PTL on these cells. The effects of PTL on the CD34+/CD19+ population were similar to that observed with the unsorted leukaemia cells. The CD34+/CD19− population was completely resistant to treatment with PTL, with more cells surviving treatment than the unsorted cells (P=0.03). In the 7 responding cases, the viability of the unsorted cells decreased to 28.4±7.1% and 38±12% were apoptotic following treatment. Very similar effects were observed with the CD34+/CD19+ subfraction in these responding cases with viability reduced to 33.4±6% and 35.9±14% were apoptotic. In contrast, the CD34+/CD19− cells from these 7 cases were significantly resistant to PTL with viabilities >75% at all concentrations evaluated (P<0.003). Apoptosis was 2.6-fold lower at 10μM PTL in the CD34+/CD19− subfraction compared to the unsorted cells (P=0.05). FISH analyses were performed on the viable cells at the end of the time-course and confirmed that leukaemia cells were surviving treatment with PTL. CD34+/CD38− cells from normal peripheral blood samples were also found to be resistant to treatment with PTL and survival of these cells at 10μM was not significantly different to that observed in the CD34+/CD19− ALL population in all 11 cases (P=0.38). Studies to assess the functional capacity of PTL-treated ALL cells are ongoing. These data demonstrate that while PTL shows promising effects on the bulk leukaemia population in some ALL cases, it had no significant effect on the putative ALL stem cell population. In each case examined, the CD34+/CD19− cells were resistant to short term exposure to PTL and responded in a similar manner to normal haemopoietic stem cells. These findings highlight the importance of evaluating therapeutic agents in the context of leukaemia stem cell populations and not just on the bulk leukaemia. Future studies are warranted to gain insight into how the drug sensitivity of ALL stem cells may be mediated.

scholarly journals Myeloid antigen co-expression in childhood acute lymphoblastic leukaemia: relationship with in vitro drug resistance

1999 ◽  
Vol 105 (4) ◽  
pp. 876-882 ◽  
Author(s):  
M. L. Den Boer ◽  
P. Kapaun ◽  
R. Pieters ◽  
K. M. Kazemier ◽  
G. E. Janka-Schaub ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Acute Lymphoblastic Leukaemia ◽  
Lymphoblastic Leukaemia ◽  
Childhood Acute Lymphoblastic Leukaemia
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