scholarly journals Therapeutic delivery of siRNA with polymeric carriers to down-regulate STAT5A expression in high-risk B-cell acute lymphoblastic leukemia (B-ALL)

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0251719
Author(s):  
Mahsa Mohseni ◽  
Cezary Kucharski ◽  
Remant Bahadur K. C. ◽  
Mohammad Nasrullah ◽  
Xiaoyan Jiang ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Cell Growth ◽  
Delivery System ◽  
Lymphoblastic Leukemia ◽  
Delivery Systems ◽  
Target Cells ◽  
Promising Therapeutic Approach ◽  
Polymeric Delivery ◽  
Sirna Therapy ◽  
Stat5a Gene

Overexpression and persistent activation of STAT5 play an important role in the development and progression of acute lymphoblastic leukemia (ALL), the most common pediatric cancer. Small interfering RNA (siRNA)-mediated downregulation of STAT5 represents a promising therapeutic approach for ALL to overcome the limitations of current treatment modalities such as high relapse rates and poor prognosis. However, to effectively transport siRNA molecules to target cells, development of potent carriers is of utmost importance to surpass hurdles of delivery. In this study, we investigated the use of lipopolymers as non-viral delivery systems derived from low molecular weight polyethylenimines (PEI) substituted with lauric acid (Lau), linoleic acid (LA) and stearic acid (StA) to deliver siRNA molecules to ALL cell lines and primary samples. Among the lipid-substituted polymers explored, Lau- and LA-substituted PEI displayed excellent siRNA delivery to SUP-B15 and RS4;11 cells. STAT5A gene expression was downregulated (36–92%) in SUP-B15 and (32%) in RS4;11 cells using the polymeric delivery systems, which consequently reduced cell growth and inhibited the formation of colonies in ALL cells. With regard to ALL primary cells, siRNA-mediated STAT5A gene silencing was observed in four of eight patient cells using our leading polymeric delivery system, 1.2PEI-Lau8, accompanied by the significant reduction in colony formation in three of eight patients. In both BCR-ABL positive and negative groups, three of five patients demonstrated marked cell growth inhibition in both MTT and trypan blue exclusion assays using 1.2PEI-Lau8/siRNA complexes in comparison with their control siRNA groups. Three patient samples did not show any positive results with our delivery systems. Differential therapeutic responses to siRNA therapy observed in different patients could result from variable genetic profiles and patient-to-patient variability in delivery. This study supports the potential of siRNA therapy and the designed lipopolymers as a delivery system in ALL therapy.

scholarly journals Low molecular weight B cell growth factor induces proliferation of human B cell precursor acute lymphoblastic leukemias

Blood ◽  
1987 ◽  
Vol 70 (1) ◽  
pp. 132-138 ◽  
Author(s):  
B Wormann ◽  
SR Mehta ◽  
AL Maizel ◽  
TW LeBien
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Growth Factor ◽  
Cell Growth ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Cell Precursor ◽  
B Cell Growth Factor ◽  
B Cell Precursors

Experiments were conducted to determine the effect of low mol wt B cell growth factor (L-BCGF) on B cell precursor acute lymphoblastic leukemia (ALL). L-BCGF induced a significant increase in 3H-TdR incorporation in 28 of 37 bone marrow aspirates from patients with B cell precursor ALL, with stimulation indices ranging from 2 to 129. Fluorescence-activated cell sorting confirmed that in five of seven patients the common acute lymphoblastic leukemia antigen (CALLA)/CD10 positive leukemic cells were responding directly to L-BCGF. L-BCGF was capable of inducing, in some patients, an increase in absolute viable cells and could also induce colony formation in vitro. The response of B cell precursor ALL was not attributable to beta IL 1, IL 2, or gamma interferon. These results indicate that the majority of B cell precursor ALL undergo a proliferative response to L-BCGF, suggesting a regulatory role for this lymphokine in the growth of B cell precursors.

Cytokine Gene Polymorphisms in Turkish Patients with Childhood Acute Lymphoblastic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4441-4441
Author(s):  
Kursat Ozdilli ◽  
Fatma Oguz ◽  
Hulya Bilgen ◽  
Yeliz Duvarci ◽  
Halim Issever ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Odds Ratio ◽  
Lymphoblastic Leukemia ◽  
The Other ◽  
Control Group ◽  
Target Cells ◽  
Cytokine Gene ◽  
Chi Square ◽  
Other Hand ◽  
Ifn Γ

Abstract Cytokines are chemical mediators between cells and they bind on their own specific receptors on the target cells. Cytokine gene polymorphism may be implicated in the pathogenesis of infections autoimmun disease and malignancies via their effect on cytokine production and regulation. Leukemic cells proliferate under the influence of cytokines. It is known that acute lymphoblastic leukemia (ALL) which is sensitive to some cytokine gene is one of the hematological malignances derived from lymphoid tissue. Our aim is to determined frequencies of selected cytokines (TNF-α, TGF-β, IL-10, IL-6, IFN-γ) in childhood ALL patients and unrelated healthy control groups. We also investigated weather these polymorphism might contribute to the pathogenesis of ALL. Method: Genotyping was performed by polymerase chain reaction with sequence specific primers (PCR-SSP) using “ One lamda” kit in 44 ALL patients and 50 unrelated healthy individuals. Allelic frequencies were determined 24 polymorphism located within 16 cytokine genes. Genotype frequencies between ALL patients and controls were compared using Chi-Square Yates, Fisher’s Exact Tests and Stepwise Logistic Regression Analysis (SLRA). Results: The frequency of TGF-β(TT/GG) allel (29,5% versus 8%, respectively;in chi-square p=0,007,odds ratio=4,82, 95% confidence interval (CI) 1,49–16,16; in SLRA p=0,002, OR=15,26,95% CI 2,77–84,05), TGF-β(TC/GG) allel (36,4% versus 10%, respectively; in chi-square p=0,002,odds ratio=5,14, 95% CI 1,69–15,59; in SLRA p=0,005,OR=10,21, 95% CI 2,02–51,61), IL-6(GC) allel (38,6% versus 8%, respectively; in chi-square p<0,001; odds ratio 7,24; 95% CI 2,20–23,76; in SLRA p=0,02,OR=6,37, 95% CI 1,22–33,15), IL-10(GCC/ATA) allel (36,4% versus 8%, respectively; in chi-square p=0,001, odds ratio 6,57, 95% CI 1,99–21,64; in SLRA p=0,01,OR=8,04, 95% CI 1,40–46,04), IFN-γ(TA) allel (54,5% versus 10%, respectively; in chi-square p<0,001, odds ratio 10,8, 95% CI 3,60–32,40; in SLRA p<0,001,OR=29,43, 95% CI 5,47–158,35) frequencies were found higher in patients with ALL compared to the control group. On the other hand IFN-γ(TT) allel (20% versus 48%, respectively; p=0,005; odds ratio 0,27; 95% CI 0,11–0,70), IFN-γ(AT)(0% versus 22%, respectively; p=0,001; odds ratio 1,28; 95%CI 1,10–1,48; fisher’s exact=0,001) and IL-6(CA)(0% versus 22%, respectively; in chi-square p<0,001; odds ratio 1,28; 95% CI 1,10–1,28; fisher’s exact=0,001) allel frequencies were found higher in the control group compared to the patients with ALL.TNF-α(GG) allel frequency was higher both in patients with ALL and in the control group (72% versus 85%). As a conclusion higher frequency in TGF-b(TT/GG),TGF-b(TC/GG),IL-6(GC), IL-10(GCC/ATA) and IFN-g(TA) allels may predispose to ALL.On the other hand IFN-g(TT), IFN-g(AT) and IL-6(CA) allels might be the preventive factor for ALL The present study is rather significant that it is the study which assessed the relation of the cytokines in patients with ALL compared to the control group taken from the genetic pool of The Turkish population but larger groups of studies must be done in future.

Notch Signaling Represses Mir-223 in T-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4630-4630
Author(s):  
Samuel D Gusscott ◽  
Florian Kuchenbauer ◽  
Andrew P Weng
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Cell Growth ◽  
Notch Signaling ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Gamma Secretase ◽  
Protein Levels ◽  
Cell Acute Lymphoblastic Leukemia ◽  
T Cell Leukemogenesis

Abstract Abstract 4630 T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer of immature T cells that often shows aberrant activation of the Notch1 signaling pathway. Several studies have utilized mRNA expression profiling to identify downstream mediators of oncogenic Notch signaling in this context. Since microRNAs (miRNAs) have in recent years been shown to play important roles in hematological maliganancy, we performed a microarray-based screen for Notch-dependent miRNA expression in T-ALL. Jurkat and P12-Ichikawa cell lines were treated with gamma-secretase inhibitor to block Notch signaling vs. DMSO control for 4 days and profiled using Exigon miRCURY LNA miRNA microarrays. Surprisingly few miRNAs were found to be regulated by this approach; however, one of the hits, miR-223, showed consistent upregulation after gamma-secretase treatment in Jurkat cells and 5 additional human T-ALL cell lines assessed by miRNA qPCR. This observation was unique to human T-ALL as murine models of T-ALL showed no evidence for Notch-dependent miR-223 expression. Given that canonical Notch signaling results in transcriptional activation, our observation that Notch signaling is associated with reduced miR-223 expression suggests an intermediary repressor may be involved. miR-223 has been reported to play an important role in normal granulopoiesis, to be expressed relatively highly in T-ALL with myeloid-like gene features, and most recently to accelerate Notch-mediated T-cell leukemogenesis. To explore potential functional consequences for Notch-dependent miR-223 repression in T-ALL, candidate miR-223 targets identified by TargetScan software were analyzed with Ingenuity Pathway Analysis software, which indicated IGF-1, insulin receptor, PTEN, and ERK5 signaling pathways as the top hits. We recently reported IGF1R signaling to be important for growth and viability of bulk T-ALL cells as well as for leukemia-initiating cell activity. Additionally, we reported that Notch signaling directly upregulates IGF1R transcription by binding to an intronic enhancer which is present between exons 21/22 in the human, but not mouse IGF1R locus. As miR-223 has previously been reported to target IGF1R mRNA and reduce its translation, we hypothesized that Notch signaling may also upregulate net IGF1R protein expression by repressing miR-223. To test this hypothesis, we transduced several human T-ALL cell lines with miR-223 retrovirus and observed a modest decrease in total IGF1R protein levels by western blot; however, no significant change was observed in surface IGF1R levels as assessed by flow cytometry. Addtionally, knockdown of miR-223 by lentiviral expression miR-223 target sequences (miR-223 “sponge”) resulted in modestly increased total IGF1R protein levels, but again showed no demonstrable effect on surface IGF1R levels. Of note, we also observed no apparent effect of either overexpression or knockdown of miR-223 on bulk cell growth or viability. We interpret these findings to suggest that Notch signaling does not have major effects on the miR transcriptome, and that up- or down-modulation of miR-223 in established T-ALL cells does not have significant effects on overall cell growth/viability. Further studies will be required to determine if miR-223 may act in concert with other Notch target genes to modulate cell physiology. Disclosures: No relevant conflicts of interest to declare.

Natural Killer Cells In Pediatric Acute Lymphoblastic Leukemia Patients At Diagnosis Demonstrate An Inhibitory Phenotype and Reduced Cytolytic Capacity

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1397-1397 ◽  
Author(s):  
Rayne H. Rouce ◽  
Takuya Sekine ◽  
Gerrit Weber ◽  
Claude Chew ◽  
Katayoun Rezvani ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Nk Cells ◽  
Nk Cell ◽  
Lymphoblastic Leukemia ◽  
Target Cells ◽  
Healthy Controls ◽  
Cytokine Release ◽  
Absolute Count ◽  
Flow Cytometric ◽  
Pediatric All

Abstract Background Natural killer (NK) cells are a key component of innate immunity, with the potential to recognize and kill transformed malignant cells without prior sensitization. A balance between activating and inhibitory signals from cell surface receptors determines NK cell cytotoxicity and cytokine release. Therapeutic approaches to augmenting NK cell function are being explored in various malignancies. Little is known about NK phenotype and function in patients with childhood acute lymphoblastic leukemia (ALL), the most common childhood cancer. Here we describe an inhibitory phenotype and impaired cytolytic function in NK cells from pediatric ALL patients at diagnosis, compared with healthy pediatric controls. Restoring NK function may be a useful therapeutic approach in ALL. Methods Peripheral blood mononuclear cells (PBMCs) were isolated from 25 patients with newly diagnosed B-ALL, age 1-16 years, and 7 healthy controls, age 2-13 years, in order to compare NK cell frequency, immunophenotype, and functional activity. NK frequency was assessed by flow cytometric staining for CD56+CD3- cells. NK phenotype was assessed by surface expression of activating receptors NKp30, NKp44, NKp46 and NKG2D and inhibitory receptors KIR2DL1/S1, KIR2DL2/S2, KIR3DL1 and NKG2A. Functional activity was determined by incubation of NKs with target cells, followed by flow cytometric measurement of degranulation (surface CD107a) and cytokine release (intracellular IFNg and TNFa). Targets included the MHC class I deficient K562 cell line and, where available, autologous ALL blasts. Results ALL patients demonstrated significantly lower absolute NK cell counts compared with healthy controls (mean absolute count 168 vs. 406 cells/uL, p = 0.0002). They also exhibited significantly fewer NK cells expressing the activating marker NKp46 (mean absolute count 70 vs. 165, p = 0.016); and a significantly higher percentage of cells expressing the inhibitory marker NKG2A (mean 20.5% vs. 1.95% in controls, p = 0.012) (Fig 1A). In co-culture assays with K562 target cells, ALL patients' NK cells demonstrated inferior degranulation and cytokine release compared to healthy controls (representative data in Fig 1B; mean IFNγ production of 1.2% vs. 4.8%, p = 0.02; mean TNFα production of 1.8% vs. 3.8%, p = 0.06; and mean surface CD107a of 5.4% vs. 15.1%, p = 0.08). ALL samples (n = 3) demonstrated little to no cytokine release when incubated with autologous blasts compared with the response elicited by PMA-ionomycin (representative data in Fig 1C; mean CD107a 0.92% vs. 7.85%, p = 0.04; mean IFNγ 0.26% vs 40.47%, p = 0.10; mean TNFα 0.2% vs 41%, p = 0.008). Conclusion At diagnosis, pediatric ALL patients exhibit a lower frequency of NK cells, an inhibitory phenotype, and decreased cytolytic activity compared to healthy pediatric controls, particularly against autologous leukemic blasts. These results suggest that augmentation of the NK response may be useful therapeutically to improve outcomes in childhood ALL. Disclosures: No relevant conflicts of interest to declare.

Down-Regulation of Mir-26b and Its Inhibition on the Growth of T Cell Acute Lymphoblastic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2440-2440
Author(s):  
Tian Yuan ◽  
Yaling Yang ◽  
Jeffrey You ◽  
Daniel Lin ◽  
Kefeng Lin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Cell Growth ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Expression Level ◽  
Rt Pcr ◽  
Altered Expression ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Introduction: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy accounting for 15% of pediatric and 25% of adult acute lymphoblastic leukemia (ALL) cases. With current chemotherapies and transplantation therapy, there are still 25-50% T-ALL patients that suffer from relapse and have a poor outcome. MicroRNAs (miRNAs or miRs) are endogenous small non-coding RNAs (containing about 22 nucleotides in length). miRs function at posttranscriptional level as negative regulators of gene expression and exert their regulatory function through binding to target mRNAs and silencing gene expression. To better understand the pathogenesis and develop the new therapeutic targets of T-ALL, we have developed a Pten tumor suppressor knockout T-ALL mouse model and profiled miRs from the mouse Pten deficient T-ALL. miR-26b was one of the miRs that were found down-regulated in the mouse Pten deficient T-ALL. Recent studies showed that the aberrant expression of miR-26b is implicated in several types of cancer. The expression level of miR-26b and its role of in T-ALL, however, are unknown. We investigated if the expression level of miR-26b is aberrant in T-ALL and the effect of potentially altered expression on the growth of human T-ALL cells. Methods: We conducted miR array profiling to identify differentially expressed miRs in the mouse Pten deficient T-ALLs compared with preneoplastic thymocyte controls. We validated expression levels of several miRs, including miR-26b, that are differentially expressed in mouse and human T-ALL cells using quantitative RT-PCR. We also overexpressed miR-26b using a lentivirus based vector in human T-ALL cell lines to assess its effect on cell growth and apoptosis. Results: Employing miR array profiling, we identified a subset of miRs that exhibited marked altered expression in the mouse Pten deficient T-ALL cells. Quantitative RT-PCR validated that the expression level of miR-26b in the mouse Pten deficient T-ALL cells was markedly lower in comparison to that of preneoplastic thymocytes. To determine if miR-26b expression level is also altered in human T-ALL, we performed quantitative RT-PCR on a panel of human T-ALL cell lines. Indeed, the expression level of miR-26b is significantly lower in the human T-ALL cell lines when compared with that of normal thymocytes. To functionally assess if miR-26b plays a role in the cell growth of human T-ALL cells, we expressed exogenous miR-26b in a panel of human T-ALL cell lines. We demonstrated that the expression of exogenous miR-26b significantly reduced the proliferation and promoted apoptosis of several human T-ALL cell lines. Conclusions: Our results demonstrated that miR-26b is down-regulated in T-ALL and the expression of exogenous miR-26b elicits deceased cell proliferation and increased apoptosis of human T-ALL. These results suggest that miR-26b may function as a tumor suppressor in the development of T-ALL and further characterization of the target and regulation of miR-26b may have therapeutic implications. Disclosures No relevant conflicts of interest to declare.

scholarly journals Doxorubicin/Nucleophosmin Binding Protein-Conjugated Nanoparticle Enhances Anti-leukemia Activity in Acute Lymphoblastic Leukemia Cells in vitro and in vivo

2021 ◽  
Vol 12 ◽  
Author(s):  
Donghui Gan ◽  
Yuwen Chen ◽  
Zhengjun Wu ◽  
Liping Luo ◽  
Shimuye Kalayu Yirga ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Acute Lymphoblastic Leukemia ◽  
Drug Delivery System ◽  
Delivery System ◽  
Binding Protein ◽  
Lymphoblastic Leukemia ◽  
Multidrug Resistant ◽  
Apoptosis Induction

Acute lymphoblastic leukemia (ALL) is an aggressive malignancy. Adults with ALL have more than 50% relapse rates. We have previously validated that overexpression of nucleophosmin (NPM) is involved in the multidrug resistance (MDR) development during ALL; and a synthetically engineered recombinant NPM binding protein (NPMBP) has been developed in our group; NPMBP and doxorubicin (DOX) can be conjugated in a nanoparticle-based drug delivery system named DOX-PMs-NPMBP to counteract MDR during ALL. Here, we evaluated the antileukemia potential of DOX-PMs-NPMBP in resistant ALL cells. This study demonstrates that DOX-PMs-NPMBP significantly enhances chemosensitivity to DOX in ALL cells. Despite at variable concentrations, both resistant and primary ALL cells from relapsed patients were sensitive to DOX-PMs-NPMBP. In detail, the half maximal inhibitory concentration (IC50) values of DOX-PMs-NPMBP were between 1.6- and 7.0-fold lower than those of DOX in cell lines and primary ALL cells, respectively; and apoptotic cells ratio was over 2-fold higher in DOX-PMs-NPMBP than DOX. Mechanistically, p53-driven apoptosis induction and cell cycle arrest played essential role in DOX-PMs-NPMBP-induced anti-leukemia effects. Moreover, DOX-PMs-NPMBP significantly inhibited tumor growth and prolonged mouse survival of ALL xenograft models; and no systemic toxicity occurrence was observed after treatment during follow-up. In conclusion, these data indicate that DOX-PMs-NPMBP may significantly exert growth inhibition and apoptosis induction, and markedly improve DOX antileukemia activity in resistant ALL cells. This novel drug delivery system may be valuable to develop as a new therapeutic strategy against multidrug resistant ALL.

In Vitro Effects of PI3Kδ Inhibitor GS-1101 (Cal-101) in Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3534-3534 ◽  
Author(s):  
Nathalie Y Rosin ◽  
Stefan Koehrer ◽  
Ekaterina Kim ◽  
Susan O'Brien ◽  
William G. Wierda ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Acute Lymphoblastic Leukemia ◽  
Cell Growth ◽  
B Cell ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Lymphocytic Leukemia ◽  
P Value ◽  
B Cell Malignancies ◽  
Growth Experiments

Abstract Abstract 3534 Acute lymphoblastic leukemia (ALL) is a highly heterogeneous disease. B-cell acute lymphoblastic leukemia (B-ALL) is characterized by uncontrolled proliferation of immature lymphoid blasts with suppression of normal hematopoiesis. Phosphoinositide 3-kinases (PI3K) transmit activation signals from diverse transmembrane receptors, leading to generation of phosphatidylinositol- 3,4,5-trisphosphate (PIP3) which promotes proliferation, differentiation, migration, and survival in lymphocytes and various other cell types. A knockout mouse model of the PI3K isoform p110δ demonstrates a unique role of p110δ (PI3Kδ) in B cell receptor (BCR) signaling. This is corroborated by clinical efficacy of the PI3Kδ inhibitor GS-1101 in mature B cell malignancies, especially in chronic lymphocytic leukemia (CLL). In contrast to mature B cell malignancies, expression and function of PI3Kδ in B-ALL has not been well characterized. We therefore analyzed PI3Kδ expression and effects of the PI3Kδ inhibitor GS-1101 in B-ALL. To screen efficacy of GS-1101 in B-ALL subsets, we performed viability and proliferation assays, using a panel of B-ALL cell lines, derived from different B-cell development stages (Pro-B: REH, RS4;11, Nalm-20, Nalm-21, TOM-1; Pre-B: Nalm-6, Kasumi-2, KOPN-8, SMS-SB, RCH-ACV, 697; Mature: Tanoue, Ball-1 unknown: CCRF-SB). A key downstream effector of PI3K is the serine/threonine kinase Akt, whose phosphorylation is used as a common readout of PI3K activation status. Western Blot analysis of the 15 cell lines showed almost identical levels of phospho-Akt (Ser473) in all tested cell lines, suggesting constitutive PI3K activity. To investigate the ability of GS-1101 to inhibit B-ALL cell proliferation, we performed cell growth experiments. Among the pre-B cell lines 4 of 6 showed a marked decrease in proliferation, 2 other pre-B cell lines showed a minor decrease. In contrast, none of the pro-B or mature B-ALL cell lines were affected by GS-1101. To explore the effects of GS-1101 on cell cycle of B-ALL cells, cell lines were treated with GS-1101 at concentrations ranging from 0.5μM to 5μM. In accordance with the cell growth experiments, G1 phase arrest and reduced numbers of S phase cells were detected in pre-B cell lines after GS-1101 treatment, but not in the pro-B or mature B cell lines. Next, we examined GS-1101 effects on metabolism of B-ALL cells via XTT (sodium 2,3,-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)-carbonyl]-2H-tetrazolium inner salt) staining. Cell lines were treated with GS-1101 concentrations between 0.1μM and 5μM for 3 days prior to XTT measurement. Pre-B cells showed a significant (p-value <0.0001) decrease in normalized absorbance compared to the control (without treatment) indicating a decrease in cellular viability. Finally, preliminary co-culture experiments of primary B-ALL samples and KUSA-H1 bone marrow stromal cells revealed significantly reduced B-ALL cell viability after GS-1101 treatment, signifying that GS-1101 can overcome microenviromental-mediated B-ALL cell protection; this is similar to that in other B cell malignances. In summary, these experiments demonstrate that GS-1101 inhibits growth, cell cycle progression and metabolic activity of pre-B ALL cells. Validation of these data with primary patient samples is ongoing. Disclosures: Lannutti: Gilead Sciences Inc: Employment.

Troglitazone Inhibits Cell Growth and Induces Apoptosis of B-Cell Acute Lymphoblastic Leukemia Cells with t(14;18)

2006 ◽  
Vol 116 (1) ◽  
pp. 30-40 ◽  
Author(s):  
M. Takenokuchi ◽  
K. Saigo ◽  
Y. Nakamachi ◽  
S. Kawano ◽  
M. Hashimoto ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Cell Growth ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cells ◽  
Cell Acute Lymphoblastic Leukemia

scholarly journals Prevalence and Growth Characteristics of Malignant Stem Cells in B-Lineage Acute Lymphoblastic Leukemia

Blood ◽  
1997 ◽  
Vol 89 (10) ◽  
pp. 3735-3744 ◽  
Author(s):  
Hikari Nishigaki ◽  
Chikako Ito ◽  
Atsushi Manabe ◽  
Masa-aki Kumagai ◽  
Elaine Coustan-Smith ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Lymphoblastic Leukemia ◽  
Cell Growth ◽  
Single Cells ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cell ◽  
Growth Characteristics ◽  
Leukemic Cells ◽  
Paracrine Factors ◽  
B Lineage

We used a stroma-supported culture method to study the prevalence and growth characteristics of malignant stem cells in acute lymphoblastic leukemia (ALL). In 51 of 108 B-lineage ALL samples, bone marrow-derived stroma not only inhibited apoptosis of ALL cells but also supported their proliferation in serum-free medium. When single leukemic cells were placed in the stroma-coated wells of microtiter plates, the percentage of wells with leukemic cell growth after 2 to 5 months of culture ranged from 6% to 20% (median, 15%; 5 experiments). The immunophenotypes and genetic features of cells recovered from these cultures were identical to those noted before culture. All cells maintained their stroma dependency and self-renewal capacity. Leukemic clones derived from single cells contained approximately 103 to 106 cells after 1 month of culture; other clones became detectable only after prolonged culture. Cell growth in stroma-coated wells correlated with the number of initially seeded cells (1 or 10; r = .87). However, the observed percentages of positive wells seeded with 10 cells always exceeded values predicted from results with single-cell–initiated cultures (P < .003 by paired t-test), suggesting stimulation of leukemic cell growth by paracrine factors. In conclusion, the proportion of ALL cells with clonogenic potential may be considerably higher than previously thought.

scholarly journals ENO2 Promotes Cell Proliferation, Glycolysis, and Glucocorticoid-Resistance in Acute Lymphoblastic Leukemia

2018 ◽  
Vol 46 (4) ◽  
pp. 1525-1535 ◽  
Author(s):  
Cheng-cheng Liu ◽  
Hua Wang ◽  
Wei-da Wang ◽  
Liang Wang ◽  
Wen-jian Liu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Acute Lymphoblastic Leukemia ◽  
Cell Growth ◽  
Mrna Expression ◽  
Molecular Mechanisms ◽  
Glycogen Synthase ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Glucocorticoid Resistance ◽  
Cell Counting

Background/Aims: The metabolic features of cancer cells have long been acknowledged to be altered and to provide new therapeutic opportunities. The expression of glycolytic enzyme enolase 2 (ENO2) was found to be closely associated with the clinical features of acute lymphoblastic leukemia (ALL) patients, but its functions remain unclear in ALL. Methods: We evaluated the association between ENO2 mRNA expression in bone marrow mononuclear cells (BM-MNCs) and the efficacy of chemotherapy, and further explored the function of ENO2 in ALL. The molecular mechanisms of ENO2 expression and its effects on cell growth, glycolysis and glucocorticoid resistance were explored by Cell Counting Kit-8, glucose-consumption assay, Quantitative RT-PCR, Western blotting and in vivo tumorigenesis in NOD/SCID mice. Results: The results showed that ENO2 mRNA expression in BM-MNCs was significantly decreased when patients completed induction chemotherapy and reached complete remission (CR). ENO2 mRNA expression was increased when patients suffered relapse. Functional studies demonstrated that ENO2 promoted cell growth, glycolysis, and glucocorticoid resistance, all of which were effectively inhibited when ENO2 was silenced with shRNAs. Further studies revealed that ENO2 up-regulated various glycolysis-related genes and enhanced Akt activity with subsequent glycogen synthase kinase3β (GSK-3β) phosphorylation, inducing cell proliferation and glycolysis. The combination of silencing ENO2 and 2-deoxyglucose (2-DG) synergistically inhibited leukemia cell survival. Conclusions: These results indicate that ENO2 may be a biological marker for monitoring chemotherapeutic efficacy and relapse in ALL. ENO2 may provide a potential therapeutic strategy for ALL.

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