Overcoming Chemotherapy Resistance in Childhood Acute Lymphoblastic Leukemia by Targeting Ion Channels.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3085-3085 ◽  
Author(s):  
Serena Pillozzi ◽  
Marika Masselli ◽  
Emanuele De Lorenzo ◽  
Emanuele Cilia ◽  
Olivia Crociani ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Drug Resistance ◽  
Acute Lymphoblastic Leukemia ◽  
Ion Channels ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Chemotherapy Resistance ◽  
Significant Proportion ◽  
Protective Mechanism ◽  
Integrin Subunit

Abstract Abstract 3085 Poster Board III-22 Despite improvements in cure rates, chemotherapy resistance remains a major obstacle to successful treatment in a significant proportion of children with acute lymphoblastic leukemia (ALL), particularly in those with relapsed ALL. Bone marrow mesenchymal cells (MSC) can contribute to generate drug resistance in leukemic cells and several mechanisms have been proposed to explain this effect such as molecular interactions between stroma-derived factor 1a (SDF-1a) and its receptor CXCR4 that could trigger integrin engagement and activation of the downstream signaling cascades which would promote survival of leukemia cells. Recent evidence indicates that integrins can form macromolecular complexes with ion channels, and that the resulting integrin/channel complex can regulate cell survival. Among ion channels, those encoded by the ether-a-gò-gò-related gene 1, hERG1 channels, have been shown to form protein complexes with integrins in several tumor cell types. In experiments with the ALL cell lines REH, RS4;11 and 697 we found that ALL cell contact with MSC induced the expression of a plasma membrane signaling complex constituted by hERG1 channels, the b1 integrin subunit and the chemokine receptor CXCR4 on the surface of ALL cells. This protein complex triggered the activation of pro-survival intracellular signaling pathways. We found that hERG1 channels are central to this protective mechanism. The three cell lines and all cases (n = 63) of primary ALL expressed hERG1; exposure to hERG1 blockers could abrogate the protective effect of MSC and considerably enhanced the cytotoxicity of chemotherapeutic drugs commonly used to treat ALL, such as doxorubicin, prednisone and methothrexate. Indeed, MSC-mediated chemoresistance could be overcome by several hERG1 blockers, including classical class III antiarrhythmics, such as E4031 and Way 123,398, as well as other agents classified as hERG1-blocking drugs, such as sertindole and erythromycin. These results were observed in both ALL cell lines and primary ALL cells and were corroborated by studies in murine models of ALL. In particular, hERG1 blockers could overcome MSC-mediated drug resistance of ALL cells engrafted in immunodeficient mice: mice treated with hERG1 blockers had a marked increase in the rate of apoptosis of ALL cells in the bone marrow, a reduced leukemia burden and ALL infiltration of the liver and spleen. Notably, hERG1 blockers also improved the anti-leukemic effect of corticosteroids in mice injected with corticosteroid-resistant cells (the cell line REH). In fact E4031 reduced bone marrow engraftment, and this effect was related to an increased apoptosis of ALL cells, and was higher than that produced by dexamethasone. Treatment with dexamethasone and E4031 nearly abolished leukaemia development in mice. In sum, hERG1 blockade results impedes ALL cell growth and enhances the effect of anti-ALL chemotherapy. Because some of the hERG1 inhibitors that proved effective in this study are available for clinical use and should not carry the risk of serious cardiac arrhythmia, they should be consider for inclusion in clinical trials for drug-resistance ALL. Disclosures No relevant conflicts of interest to declare.

A Macromolecular Signaling Complex Formed by CXCR4, VLA4 and hERG1 K+ Channels Mediates Bone Marrow-Induced Chemo-Resistance in Childhood Acute Lymphoblastic Leukemias: Shortcoming Effects of hERG1 Channels Inhibitors.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1629-1629
Author(s):  
Serena Pillozzi ◽  
Marika Masselli ◽  
Amedeo Amedei ◽  
Giuseppe Gaipa ◽  
Andrea Biondi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Drug Resistance ◽  
Ion Channels ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Signalling Pathways ◽  
Dramatic Improvement ◽  
Integrin Subunit ◽  
K Channels ◽  
Survival Signals

Abstract Childhood Acute lymphoblastic leukemia (ALL) has experienced a dramatic improvement in survival rates over the past 40 years. At this time, the likelihood of cure is greater than 70%. Despite such success, relapse still occurs in 25–30% of children. The major cause of treatment failure is intrinsic or acquired drug resistance. It has been reported that stromal cells of the bone marrow (BMSC) provide a sanctuary in which subpopulations of leukaemia cells can evade chemotherapy-induced death and acquire a drug-resistant phenotype. This explains why, when ALL cell lines are cultured on human BMSC, the apoptotic effect of chemotherapic drugs is strongly inhibited. The mechanisms of BMSC-mediated protection involve a complex interplay among stroma-derived factors, in particular the SDF-1a and the chemokine receptor CXCR4. For these reasons, CXCR4-targeting compounds are nowadays considered potential therapeutic tools in ALL (Burger JA and Burkle A, Br J Haematol137: 288–296, 2007). An additive mechanism of BMSC-induced protection involeves the interaction between adhesion receptors on leukaemia cells and adhesion molecules, like fibronectin, on the surface of BMSC (Tabe Y et al, Cancer Res67:1238–1250, 2007). Recent evidence indicates that integrins trigger survival signals since they form macromolecular complexes with plasma membrane proteins. A novel integrin partner in such complexes is represented by ion channel proteins. The channel protein is not merely a bystander interactor, but it often feeds back by controlling integrin activation and downstream signaling (Arcangeli A et al, Trends Cell Biol16:631–639, 2006). This mechanisms can give a molecular explanation to the recent evidences that ion channels, especially K+ channels, mark and regulate specific stages of cancer progression, and hence may represent novel targets for cancer therapy. (Becchetti A. and Arcangeli A., J. Gen. Physiol.,28: 313–314, 2008). Among ion channels, hERG1 channels, are capable of forming multiprotein complexes with integrins in tumor cells. We report here the discovery of a peculiar multiprotein complex formed by CXCR4 and the b1 integrin subunit, besides hERG1 channels, occurring in B-ALL cells. The assembly of the complex is stimulated by adhesion onto BMSC, and is further modulated by SDF-1a. Furthermore, the hERG1/beta1/CXCR4 complex triggers the activation of different intracellular signalling pathways (MAPK activation, pAKT phosphorylation). All the BMSC-induced signalling pathways are strongly inhibited by hERG1 channel blockers. Finally, when cultured on BMSC, all the B-ALL cell lines experienced a strong reduction of apoptosis after treatment with chemotherapic drugs (doxorubicin, prednisone, L-asparaginase, metothrexate). The addition of specific hERG1 blockers bypasses drug resistance, promptly restoring a significant apoptosis in leukemia cells. On the whole, our results allow to include hERG1 channels in a scheme where they act as upstream regulators of integrin/chemokine receptors pro survival signals. In addition data here presented indicate a potential role for hERG1 inhibitors as a novel strategy for overcoming drug resistance in the treatment of ALL.

scholarly journals CALLA-positive myeloma: an aggressive subtype with poor survival

Blood ◽  
1985 ◽  
Vol 66 (1) ◽  
pp. 229-232
Author(s):  
BG Durie ◽  
TM Grogan
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Cell Lines ◽  
Median Survival ◽  
Lymphoblastic Leukemia ◽  
Myeloma Cell ◽  
Negative Group ◽  
Poor Survival ◽  
Aggressive Subtype ◽  
Leukemia Antigen

Detailed immunotyping was carried out on 21 direct myeloma bone marrow aspirates and eight human myeloma cell lines. Four previously untreated common acute lymphoblastic leukemia antigen (CALLA)-positive myeloma patients were identified and six of eight cell lines (75%) were also positive. CALLA positivity, as part of an immature B phenotype, was found to correlate with very aggressive clinical disease: median survival six months v 56 months for the CALLA-negative group.

CpG Oligonucleotides Induce Anti-Leukemia Activity in a Syngeneic Murine Model of Acute Lymphoblastic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2830-2830
Author(s):  
Alix E. Seif ◽  
Marlo D. Bruno ◽  
Junior Hall ◽  
Valerie I. Brown ◽  
Stephan A. Grupp ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Nk Cells ◽  
Bone Marrow Cells ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Intensive Therapy ◽  
Significant Proportion ◽  
Cpg Odn

Abstract Acute lymphoblastic leukemia (ALL) accounts for 80% of all pediatric leukemias and is the most common form of childhood cancer. While most children with ALL are cured by current therapies, refractory and relapsed ALL comprise a significant proportion of all pediatric cancers. Furthermore, nearly half of all ALL diagnoses occur in adults, who carry a much poorer prognosis, with the majority dying of relapsed disease. Relapsed ALL generally requires intensive therapy with significant associated morbidity and mortality. Development of novel therapies is essential to improving outcomes. DNA oligodeoxynucleotides containing CpG motifs (CpG ODN) stimulate anti-tumor immune activity via Toll-like receptor 9 (TLR9) activation and are currently in clinical trials for a variety of solid tumors. We have previously reported that CpG ODN stimulation alters antigen presentation by human ALL cells, enhancing allogeneic Th1 responses. In addition, we have shown that CpG ODN administration in vivo reduces the leukemic burden of primary human ALL xenografts in Nod-SCID mice, and that this activity is mediated in part by NK cells. To further the development of CpG ODN as a novel therapeutic agent for ALL, we have investigated the induction of anti-ALL activity by CpG ODN in a syngeneic ALL setting. CpG ODN did not exhibit direct toxicity against cell lines derived from leukemic Eμ-ret transgenic mice in vitro, nor did it alter CD40 or CD86 expression or cytokine production. However, using a flow cytometry-based in vitro killing assay we observed CpG ODN-induced elimination of leukemia cells when cultured with splenocytes or bone marrow cells from Eμ-ret transgene-negative mice (P=0.0388). The difference between CpG ODN-treated and untreated controls became more pronounced with increasing effector:target ratios (P<0.0001). Preliminary data show that depletion of NK cells markedly decreases the magnitude of the observed effect, supporting the hypothesis that this cell type is involved in targeted control of ALL in this model. The ability of CpG ODN to exert anti-leukemia activity in a syngeneic setting suggests that it may have utility as an adjuvant therapy. To test this hypothesis we administered CpG ODN (or PBS) to syngeneic leukemia-bearing mice 2 days after completion of a chemotherapy regimen used to reduce leukemia burden. When mice were sacrificed 3 weeks after treatment, we found significantly reduced leukemia burden in bone marrow (P=0.0019), spleen (P<0.00001) and blood (P=0.00028) of CpG ODN-treated mice. Cell-depletion and cytokine-neutralization assays are currently ongoing to define the mechanism of action of CpG ODN in these settings. To our knowledge, this is the first demonstration of CpG ODN-induced anti-ALL activity in a post-chemotherapy syngeneic model, suggesting that this agent has the potential to treat minimal residual disease and to reduce the incidence of relapse.

scholarly journals Krüppel-like Factor 4 (KLF4) Suppresses T-Cell Acute Lymphoblastic Leukemia By Inhibiting Expression of MAP2K7 and Expansion of Leukemia Initiating Cells

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3569-3569
Author(s):  
Ye Shen ◽  
Chun Shik Park ◽  
Koramit Suppipat ◽  
Takeshi Yamada ◽  
Toni-Ann Mistretta ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Tumor Suppressor ◽  
Cell Lines ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cells ◽  
Brdu Incorporation ◽  
Jnk Pathway

Abstract Acute lymphoblastic leukemia (ALL) is the most common hematological malignancy in children. Although risk-adaptive therapy, CNS-directed chemotherapy and supportive care have improved the survival of ALL patients, disease relapse is still the leading cause of cancer-related death in children. Therefore, new drugs or novel multi-drug combinations are needed as frontline treatments for high-risk patients and as salvage agents for relapsed disease. T-cell ALL (T-ALL) is a subset of ALL that exhibits activating mutations of NOTCH1 in more than 50% of the patients. However, the use of gamma-secretase inhibitors to reduce NOTCH1 activity has not been successful in patients due to limited response and toxicity. Therefore, identification of genetic factors that cooperate with T-ALL leukemogenesis is needed for the development of alternative therapies. KLF4 is a transcription factor that functions as a tumor suppressor or an oncogene depending on cellular context. Our data showed significant reduction of KLF4 transcripts in lymphoblasts from T-ALL patients compared to blood and bone marrow cells from healthy individuals. In consistent with reduced KLF4 levels, these patients exhibit hyper-methylation of CpG islands located between nt -811 and +1190 relative to KLF4 transcription start site. From these findings we hypothesized that KLF4 has tumor suppressor function in T-ALL leukemogenesis. To test our hypothesis, we transduced 5-FU treated bone marrow (BM) cells from control (Klf4fl/fl), Klf4 null (Klf4fl/fl; Vav-iCre) and Klf4 heterozygous (Klf4fl/+; Vav-iCre) mice with retrovirus carrying a NOTCH1 activating mutant (L1601P-ΔP) and then transplanted these BM cells into irradiated recipient mice. In contrast to controls, mice transplanted with transduced Klf4-null BM cells developed T-ALL with significantly higher penetrance (Klf4 null 76.5% v.s. control 21.3%) and shorter latency (Klf4 null 93 days v.s. control 130 days). Interestingly, Klf4 heterozygous group shows similar survival kinetics as Klf4 null group, suggesting that Klf4 haploinsufficiency is enough to accelerate onset of leukemia. To investigate the effect of Klf4 deletion in established leukemia cells, we transplanted NOTCH1 L1601P-ΔP transduced BM cells from Klf4fl/fl; CreER+ mice to induce leukemia. Post-transplantation deletion of the Klf4 gene by tamoxifen administration was able to accelerate T-ALL development compared to mice injected with vehicle. On the cellular level, loss of KLF4 led to increased proliferation of leukemia cells as assessed by in vivo BrdU incorporation, which correlated with decreased levels of p21 protein. Limited dilution transplantation of primary leukemia cells into secondary recipients showed a 9-fold increase of leukemia initiating cells (LIC) frequency in Klf4null leukemia cells compared to controls, suggesting that KLF4 controls expansion of LIC in T-ALL. To elucidate molecular mechanism underlying KLF4 regulation in T-ALL cells, we performed microarray and ChIP-Seq in control and Klf4 null CD4+CD8+ leukemia cells. Combined analyses revealed 202 genes as KLF4 direct targets, of which 11 genes are also deregulated in human T-ALL cells by comparing with published microarray datasets. One of the top upregulated genes is Map2k7, which encodes a kinase upstream of the JNK pathway. Immunoblots in leukemia cells confirmed increased expression of MAP2K7 protein and enhanced phosphorylation of its downstream targets JNK and ATF2. To further investigate the role of JNK pathway in T-ALL, we tested JNK inhibitor SP600125 in human T-ALL cell lines (KOPTK1, DND41, CCRF-CEM, MOLT3). Interestingly, SP600125 showed dose-dependent cytotoxicity in all human T-ALL cell lines tested regardless of their NOTCH1 status. Overall our results showed for the first time that KLF4 functions as a tumor suppressor in T-ALL by regulating proliferation of leukemia cells and frequency of LIC. Additional study elucidated that KLF4 suppresses the JNK pathway via direct transcriptional regulation of MAP2K7. Moreover, the vulnerability of human T-ALL cell lines to JNK inhibition provides a novel target for future therapy in T-ALL patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Targeting Nucleolin for Reversal of Chemotherapy Resistance in Acute Lymphoblastic Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5058-5058
Author(s):  
Jianda Hu ◽  
Yanxin Chen ◽  
Zhengjun Wu ◽  
Lingyan Wang ◽  
Jingjing Wen ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Acute Lymphoblastic Leukemia ◽  
Drug Sensitivity ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Mrna Level ◽  
Chemotherapy Resistance

Chemotherapy resistance is considered to be the principal cause of ineffective treatment in acute lymphoblastic leukemia (ALL). Nucleolin (NCL) is high expression andplays oncogenic roles in most cancers. However, less research on the role of NCL in hematologic malignancies was noted. Our previous studies have showed that overexpression of NCL was associated with worse prognosis in the patients with acute leukemia and NCL expressionwashigher in resistant HL-60/ADR than in sensitive HL-60 cells. The potential mechanisms of NCL in chemotherapy resistance have yet to be revealed. Here we presented that expression of NCL was associated positively with chemotherapy resistance and poor prognosis in ALL. Overexpressed NCL at both mRNA and protein level was relevant to a poorer overall survival (OS) and relapse free survival (RFS), indicating NCL as an independent prognostic marker in ALL. mRNA level of NCL in de novo ALL was quantitatively higher than in complete remission(CR) status, and refractory/relapse ALL had the highest level. Upon above clinical data, we further investigated the mechanism(s) by which NCL regulated drug resistance in ALL cells. Remarkably, NCL expression was higher in resistant ALL cells relative to sensitive parental cells. When treated with ADM, NCL level was decreased in sensitive parental cells while unchanged in resistant cells. Overexpressing NCL suppressed drug sensitivity, altered drug effluxion and decreased intracellular drug accumulation, while inhibition of NCL led to a completely reversed appearance, more intracellular Adriamycin(ADM) mean fluorescence intensity (MFI) and percentage of ADM accumulated cells population. Overexpression of NCL increased significantly the IC50 of ADM. The IC50 of ADM on Jurkat-NCL-overexpression(OE), Jurkat-NCL-knockdown(KD), Molt-4-NCL-OE, Molt-4-NCL-KD, Nalm-6-NCL-OE, Nalm-6-NCL-KD were 1.362±0.271μg/ml, 0.077±0.010μg/ml, 4.863±0.733μg/ml, 0.081±0.018μg/ml, 0.237±0.042μg/ml and 0.046±0.002μg/ml, respectively (P <0.05). Involvement of ATP-binding cassette (ABC) transporters was proved in NCL mediated drug resistance. Silencing NCL resulted in a decrease of P-gp, MRP1, LRP and BCRP in ALL cells, and NCL overexpression increased the MRP1, LRP and BCRP. The Akt/mTOR and ERK signaling pathways were involved in this procedure. Notably, co-IP assays confirmed the NCL-Ras, NCL-ERK and NCL-BCRP interaction. For intervention study, aptamer AS1411, a NCL inhibitor, could reduce drug resistance in ALL cell lines and primary ALL cells.Moreover, AS1411 treatment decreased BCRP protein expression. Furthermore, the ALL leukemia models that nude mice engrafted with Nalm-6 cells and NCG mice engrafted with Luc+ Nalm-6 cells were established, then treated with ADM plus AS1411 or control CRO for comparison drug sensitivity and survival. Growth of subcutaneous xenograft tumors was inhibited in those treated with AS1411 or ADM, compared to their respective controls treated with CRO or PBS. The stronger inhibition effect was observed in those treated with AS1411 combined with ADM. For Luc+Nalm-6 derived ALL model, leukemia progression was suppressed in mice treated with AS1411 and AS1411 combined with ADM. AS1411and ADM, especially combination of AS1411 and ADM, could improve survival of the leukemic mice compared to those treated with PBS. The results showed that NCL targeted by AS1411 sensitized ADM treatment and prolonged survival in vivo. In summary, our findings revealed NCL as a survival predictor and the novel role of NCL in ALL chemo-resistance. NCL may be a potential target for improving outcome in ALL. Disclosures No relevant conflicts of interest to declare.

Leptomycin B Overcomes Imatinib Resistance Mediated by Stromal Cells and Mutant BCR-ABL in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2089-2089
Author(s):  
Arinobu Tojo ◽  
Kiyoko Izawa ◽  
Rieko Sekine ◽  
Tokiko Nagamura ◽  
Minoru Yoshida ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Cell Lines ◽  
Stromal Cells ◽  
Cell Layer ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Leptomycin B ◽  
Imatinib Resistance ◽  
L2 Cells

Abstract Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-ALL) is one of the most intractable hematological malignancies, and readily acquires resistance to chemotherapeutic drugs including imatinib mesylate. We hypothesized that the adhesive interaction of Ph-ALL cells with bone marrow stromal cells might cause their escape from drug-induced apoptosis and subsequent minimal residual disease, resulting in the generation of a chemoresistant clone such as a clone harboring mutant BCR-ABL. To gain insight into this possibility and a novel strategy against imatinib resistance, we used two Ph-ALL cell lines designated as IMS-PhL1 (L1) and IMS-PhL2 (L2). L1 cells had wild type BCR-ABL, whereas L2 cells had Y253H mutant and revealed 10-fold or more resistance to imatinib, compared with L1 cells. The growth of L1 cells was autonomous and their spontaneous apoptosis was suppressed by co-culture with a murine bone marrow stromal cell line, HESS-5. In contrast, the sustained growth and survival of L2 cells was absolutely dependent on direct contact with HESS-5. Both cell lines adhered to and migrated beneath the HESS-5 cell layer, resulting in the formation of cobblestone areas (CA). While floating L1 cells were eradicated by 1 mM imatinib, a portion of adherent L1 cells could survive even at 10 μM imatinib. Similarly, L2 cells forming CA beneath the HESS-5 cell layer considerably resisted prolonged exposure to 10 μM imatinib. Leptomycin B (LMB), a potent inhibitor of CRM1/exportin-1, can trap BCR-ABL in the nucleus and can aggressively eliminate BCR-ABL+ cells in combination with imatinib (Wang et al., 2001). We tested LMB for its ability to eliminate CA or adherent Ph-ALL cells in combination with imatinb. The result for L2 cells was shown in Figure. Dramatically, combined use of 10 μM imatinib and 1 nM LMB for 7 days exerted a synergistic effect on reduction in the number of CA. L1 cells were also susceptible to the combination of imatinib and LMB. Our results suggest that nuclear entrapment of BCR-ABL may be a promising strategy for overcoming imatinib resistance mediated by stromal cells as well as a certain BCR-ABL mutant. Figure Figure

Identification of Genomic Classifiers That Distinguish Induction Failure in T-Lineage Acute Lymphoblastic Leukemia in COG Study 9404.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1826-1826
Author(s):  
Stuart S. Winter ◽  
Hadya Khawaja ◽  
Zeyu Jiang ◽  
Timothy Griffin ◽  
Barbara Asselin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Drug Resistance ◽  
Acute Lymphoblastic Leukemia ◽  
Cell Lines ◽  
Expression Profiles ◽  
Lymphoblastic Leukemia ◽  
Gene Expression Profiles ◽  
Resistant Cell ◽  
Acquired Drug Resistance ◽  
Induction Failure

Abstract The clinical features of age, white count, and presence of extramedullary disease cannot predict risk for induction failure (IF) in patients who present with T-cell acute lymphoblastic leukemia (T-ALL). On the basis of recent observations that gene expression profiles can distinguish clinicopathologic cohorts of patients with acute leukemia, we hypothesized that microarray analyses performed on diagnostic T-ALL bone marrow samples might identify a genomic classifier for IF patients. Using a case-control study design for children and young adults treated for T-ALL on Children’s Oncology Group Study 9404, we analyzed 50 cryopreserved T-ALL samples using Affymetrix U133A Plus 2 genechips, which have 54,000 genes, ESTs and genomic classifiers. Following RMA normalization, we used Prognostic Multi-array Analysis (PAM) to identify a 116-member genomic classifier that could accurately identify all 6 IF cases from the 44 patients who achieved remission. Within the IF cohort, 37 genes were up-regulated and 79 were down-regulated in comparison to other outcome groups. To further investigate the genetic mechanisms governing IF, we developed four cell lines with acquired drug resistance: Jurkat and Sup T1; each having resistance to daunorubicin (DNR) and asparaginase (ASP). Using a comparative analysis for fold-change in gene expression among 6 IF patients and the T-ALL DNR and ASP-resistant cell lines, we identified seven genes that were up-regulated, and another set of seven genes that were commonly down-regulated. To validate the potential use of our 116-member gene set in predicting IF in T-ALL, we tested our genomic classifier in 42 cases which were treated on COG study 8704 and hybridized to the Affymetrix U133Av.2 chip. Because only 85 probes were shared between U133A Plus 2 and U133Av. 2 chips, we employed shrunken class centroids to constrain our classifier to 25 rank-ordered probes. This smaller classifier correctly identified the single IF case in 8704, as well as another patient who was an early treatment failure, indicating that similar genomic classifiers may identify IF patients in different clinical trials. These results indicate that genetic profiling may be useful in prospectively identifying IF patients in T-ALL. In addition, we identified genes that were commonly upregulated in IF patients and T-ALL cell lines with intrinsic drug resistance.

Chemotherapy resistance in acute lymphoblastic leukemia requires hERG1 channels and is overcome by hERG1 blockers

Blood ◽  
2011 ◽  
Vol 117 (3) ◽  
pp. 902-914 ◽  
Author(s):  
Serena Pillozzi ◽  
Marika Masselli ◽  
Emanuele De Lorenzo ◽  
Benedetta Accordi ◽  
Emanuele Cilia ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Chemokine Receptor ◽  
Molecular Mechanisms ◽  
Lymphoblastic Leukemia ◽  
Survival Rates ◽  
Chemotherapy Resistance ◽  
Leukemic Cells ◽  
Channel Blockers ◽  
Integrin Subunit ◽  
Signaling Complex

Abstract Bone marrow mesenchymal cells (MSCs) can protect leukemic cells from chemotherapy, thus increasing their survival rate. We studied the potential molecular mechanisms underlying this effect in acute lymphoblastic leukemia (ALL) cells. Coculture of ALL cells with MSCs induced on the lymphoblast plasma membrane the expression of a signaling complex formed by hERG1 (human ether-à-go-go-related gene 1) channels, the β1-integrin subunit, and the chemokine receptor CXC chemokine receptor-4. The assembly of such a protein complex activated both the extracellular signal-related kinase 1/2 (ERK1/2) and the phosphoinositide 3-kinase (PI3K)/Akt prosurvival signaling pathways. At the same time, ALL cells became markedly resistant to chemotherapy-induced apoptosis. hERG1 channel function appeared to be important for both the initiation of prosurvival signals and the development of drug resistance, because specific channel blockers decreased the protective effect of MSCs. NOD/SCID mice engrafted with ALL cells and treated with channel blockers showed reduced leukemic infiltration and had higher survival rates. Moreover, hERG1 blockade enhanced the therapeutic effect produced by corticosteroids. Our findings provide a rationale for clinical testing of hERG1 blockers in the context of antileukemic therapy for patients with ALL.

CALLA-positive myeloma: an aggressive subtype with poor survival

Blood ◽  
1985 ◽  
Vol 66 (1) ◽  
pp. 229-232 ◽  
Author(s):  
BG Durie ◽  
TM Grogan
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Cell Lines ◽  
Median Survival ◽  
Lymphoblastic Leukemia ◽  
Myeloma Cell ◽  
Negative Group ◽  
Poor Survival ◽  
Aggressive Subtype ◽  
Leukemia Antigen

Abstract Detailed immunotyping was carried out on 21 direct myeloma bone marrow aspirates and eight human myeloma cell lines. Four previously untreated common acute lymphoblastic leukemia antigen (CALLA)-positive myeloma patients were identified and six of eight cell lines (75%) were also positive. CALLA positivity, as part of an immature B phenotype, was found to correlate with very aggressive clinical disease: median survival six months v 56 months for the CALLA-negative group.

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