Multidrug resistance gene expression in acute myeloid leukemia: Major prognosis significance for in vivo drug resistance to induction treatment

1997 ◽  
Vol 74 (2) ◽  
pp. 65-71 ◽  
Author(s):  
M. Hunault ◽  
D. Zhou ◽  
A. Delmer ◽  
S. Ramond ◽  
F. Viguié ◽  
...  
Keyword(s):  
Gene Expression ◽  
Drug Resistance ◽  
Acute Myeloid Leukemia ◽  
Multidrug Resistance ◽  
Resistance Gene ◽  
Myeloid Leukemia ◽  
Induction Treatment ◽  
Multidrug Resistance Gene ◽  
Acute Myeloid

scholarly journals CD9, a potential leukemia stem cell marker, regulates drug resistance and leukemia development in acute myeloid leukemia

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yongliang Liu ◽  
Guiqin Wang ◽  
Jiasi Zhang ◽  
Xue Chen ◽  
Huailong Xu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Drug Resistance ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Stem Cell Marker ◽  
Hematopoietic Stem ◽  
Chemotherapy Drugs ◽  
And Migration ◽  
Acute Myeloid

Abstract Background Leukemia stem cells (LSCs) are responsible for the initiation, progression, and relapse of acute myeloid leukemia (AML). Therefore, a therapeutic strategy targeting LSCs is a potential approach to eradicate AML. In this study, we aimed to identify LSC-specific surface markers and uncover the underlying mechanism of AML LSCs. Methods Microarray gene expression data were used to investigate candidate AML-LSC-specific markers. CD9 expression in AML cell lines, patients with AML, and normal donors was evaluated by flow cytometry (FC). The biological characteristics of CD9-positive (CD9+) cells were analyzed by in vitro proliferation, chemotherapeutic drug resistance, migration, and in vivo xenotransplantation assays. The molecular mechanism involved in CD9+ cell function was investigated by gene expression profiling. The effects of alpha-2-macroglobulin (A2M) on CD9+ cells were analyzed with regard to proliferation, drug resistance, and migration. Results CD9, a cell surface protein, was specifically expressed on AML LSCs but barely detected on normal hematopoietic stem cells (HSCs). CD9+ cells exhibit more resistance to chemotherapy drugs and higher migration potential than do CD9-negative (CD9−) cells. More importantly, CD9+ cells possess the ability to reconstitute human AML in immunocompromised mice and promote leukemia growth, suggesting that CD9+ cells define the LSC population. Furthermore, we identified that A2M plays a crucial role in maintaining CD9+ LSC stemness. Knockdown of A2M impairs drug resistance and migration of CD9+ cells. Conclusion Our findings suggest that CD9 is a new biomarker of AML LSCs and is a promising therapeutic target.

scholarly journals Silencing long non-coding RNA XIST suppresses drug resistance in acute myeloid leukemia through down-regulation of MYC by elevating microRNA-29a expression

2020 ◽  
Vol 26 (1) ◽  
Author(s):  
Chong Wang ◽  
Lingling Li ◽  
Mengya Li ◽  
Weiqiong Wang ◽  
Yanfang Liu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Drug Resistance ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Bone Marrow Cells ◽  
Cellular Viability ◽  
Down Regulation ◽  
Acute Myeloid

Abstract Background Long non-coding RNAs (lncRNAs) are biomarkers participating in multiple disease development including acute myeloid leukemia (AML). Here, we investigated molecular mechanism of X Inactive-Specific Transcript (XIST) in regulating cellular viability, apoptosis and drug resistance in AML. Methods XIST, miR-29a and myelocytomatosis oncogene (MYC) expression in AML bone marrow cells collected from 62 patients was evaluated by RT-qPCR and Western blot analysis. Besides, the relationship among XIST, miR-29a and MYC was analyzed by dual luciferase reporter assay, RIP, and RNA pull down assays. AML KG-1 cells were treated with anti-tumor drug Adriamycin. The role of XIST/miR-29a/MYC in cellular viability, apoptosis and drug resistance in AML was accessed via gain- and loss-of-function approaches. At last, we evaluated role of XIST/miR-29a/MYC on tumorigenesis in vivo. Results XIST and MYC were up-regulated, and miR-29a was down-regulated in AML bone marrow cells. Silencing XIST inhibited cellular activity and drug resistance but promoted cellular apoptosis of KG-1 cells by down-regulating MYC. XIST inhibited miR-29a expression to up-regulate MYC. Moreover, silencing XIST inhibited tumorigenesis of AML cells in vivo. Conclusions Overall, down-regulation of XIST decreased MYC expression through releasing the inhibition on miR-29a, thereby reducing drug resistance, inhibiting viability and promoting apoptosis of AML cells.

scholarly journals MEK inhibition enhances the response to tyrosine kinase inhibitors in acute myeloid leukemia

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
María Luz Morales ◽  
Alicia Arenas ◽  
Alejandra Ortiz-Ruiz ◽  
Alejandra Leivas ◽  
Inmaculada Rapado ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Resistance Pathway ◽  
Acute Myeloid

AbstractFMS-like tyrosine kinase 3 (FLT3) is a key driver of acute myeloid leukemia (AML). Several tyrosine kinase inhibitors (TKIs) targeting FLT3 have been evaluated clinically, but their effects are limited when used in monotherapy due to the emergence of drug-resistance. Thus, a better understanding of drug-resistance pathways could be a good strategy to explore and evaluate new combinational therapies for AML. Here, we used phosphoproteomics to identify differentially-phosphorylated proteins in patients with AML and TKI resistance. We then studied resistance mechanisms in vitro and evaluated the efficacy and safety of rational combinational therapy in vitro, ex vivo and in vivo in mice. Proteomic and immunohistochemical studies showed the sustained activation of ERK1/2 in bone marrow samples of patients with AML after developing resistance to FLT3 inhibitors, which was identified as a common resistance pathway. We examined the concomitant inhibition of MEK-ERK1/2 and FLT3 as a strategy to overcome drug-resistance, finding that the MEK inhibitor trametinib remained potent in TKI-resistant cells and exerted strong synergy when combined with the TKI midostaurin in cells with mutated and wild-type FLT3. Importantly, this combination was not toxic to CD34+ cells from healthy donors, but produced survival improvements in vivo when compared with single therapy groups. Thus, our data point to trametinib plus midostaurin as a potentially beneficial therapy in patients with AML.

Cellular pharmacokinetics of daunorubicin: relationships with the response to treatment in patients with acute myeloid leukemia.

1988 ◽  
Vol 6 (5) ◽  
pp. 802-812 ◽  
Author(s):  
E Kokenberg ◽  
P Sonneveld ◽  
W Sizoo ◽  
A Hagenbeek ◽  
B Löwenberg
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Response To Treatment ◽  
Remission Induction ◽  
Pharmacokinetic Parameters ◽  
Induction Treatment ◽  
Blast Cells ◽  
Acute Myeloid

In an attempt to identify pharmacokinetic factors that determine the response of acute myeloid leukemia (AML) patients to induction chemotherapy, we determined the concentrations of daunorubicin (DNR) and the main metabolite daunorubicinol (DOL) in vivo and particularly evaluated the concentrations in blood and bone marrow nucleated cells. Cell measurements were obtained in 37 evaluable patients during their first remission induction treatment with DNR and cytarabine (ara-C) and directly compared with the plasma distribution kinetics of DNR. We show that (1) plasma DNR concentrations do not correlate with DNR concentrations in bone marrow nucleated cells; but (2) plasma area under the curve (AUC) values of DNR correlate inversely (P less than .01) with AUC values of DNR in WBCs; (3) concentrations of DNR in WBCs correlate positively (P less than .01) with DNR concentrations in bone marrow nucleated cells; and (4) the concentrations of DNR in WBCs show a negative correlation (P less than .01) with the numbers of peripheral blast cells at diagnosis. We then tested whether the pharmacokinetic parameters had predictive value for the clinical outcome of therapy, but none of the plasma levels or WBC and bone marrow concentrations of DNR predicted treatment outcome. The inverse correlation between the concentrations of DNR in WBC and the numbers of peripheral blast cells suggests that the effective DNR concentrations achieved intracellularly are mainly a function of the tumor load so that lesser amounts of DNR accumulate intracellularly when the AML cell numbers in blood are higher.

scholarly journals Dasatinib Inhibits FLT3/ITD and PTPN11mutated Acute Myeloid Leukemia Cells Overexpressing SRC Tyrosine Kinases

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1451-1451
Author(s):  
Sigal Tavor ◽  
Tali Shalit ◽  
Noa Chapal Ilani ◽  
Yoni Moskovitz ◽  
Nir Livnat ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Drug Sensitivity ◽  
Kinase Inhibitors ◽  
Advisory Committees ◽  
Acute Myeloid

Background: Recent advances in acute myeloid leukemia(AML) targeted therapy improve overall survival. While these targeted therapies can achieve prolonged remissions, most patients will eventually relapseunder therapy. Our recent studies suggest that relapse most often originates from several sub-clones of leukemic stem cells (LSCs), present before therapy initiation, and selected due to several resistance mechanisms. Eradication of these LSCs during treatment induction /remission could thus potentially prevent relapse. The overall goal of the current study was to identify drugs which can be safely administrated to patients at diagnosis and that will target LSCs. Since simultaneously testing multiple drugs in vivo is not feasible, we used an in vitrohigh throughput drug sensitivity assay to identify new targets in primary AML samples. Methods: Drug sensitivity and resistance testing (DSRT) was assessed in vitro (N=46 compounds) on primary AML samples from patients in complete remission (N=29). We performed whole exome sequencing and RNAseq on samples to identify correlations between molecular attributes and in vitro DSRT. Results:Unsupervised hierarchical clustering analysis of in vitro DSRT, measured by IC50, identified a subgroup of primary AML samples sensitive to various tyrosine kinase inhibitors (TKIs). In this subgroup, 52% (9/17) of AML samples displayed sensitivity to dasatinib (defined as a 10-fold decrease in IC50 compared to resistant samples). Dasatinib has broad TKI activity, and is safely administered in the treatment of leukemia. We therefore focused our analysis on predicting AML response to dasatinib, validating our results on the Beat AML cohort. Enrichment analysis of mutational variants in dasatinib-sensitive and resistant primary AML samples identified enrichment of FLT3/ITD (p=0.05) and PTPN11(p=0.05) mutations among dasatinib responders. Samples resistant to dasatinib were enriched with TP53 mutations (p=0.01). No global gene expression changes were observed between dasatinib-sensitive and resistant samples in our cohort, nor in the Beat AML cohort. Following this, we tested the differential expression of specific dasatinib-targeted genes between dasatinib-responding and resistant samples. No significant differences were identified. However, unsupervised hierarchical clustering of dasatinib targeted genes expression in our study and in the Beat AML cohort identified a subgroup of AML samples (enriched in dasatinib responders) that demonstrated overexpression of three SRC family tyrosine kinases:FGR, HCK and LYN as well as PTK6, CSK, GAK and EPHB2. Analysis of the PTPN11 mutant samples revealed that the IC50 for dasatinib in 23 carriers of the mutant PTPN11 was significantly lower compared to the IC50 of PTPN11 wild type samples (p=0.005). LYN was also upregulated (p<0.001) in the mutant samples. We therefore hypothesized that gene expression of dasatinib-targeted genes could be used as a predictive biomarker of dasatinib response among FLT3/ITD carriers. We found that among FLT3/ITD AML carriers in the Beat AML cohort LYN, HCK, CSK and EPHB2 were significantly over-expressed in the dasatinib responding samples (N=27) as compared to the dasatinib resistant samples (N=35). To predict response to dasatinib among FLT3/ITD carriers we used a decision tree classifier based on the expression levels of these four genes. Our prediction model yielded a sensitivity of 74% and specificity of 83% for differentiating dasatinib responders from non-responders with an AUC of 0.84. Based on our findings, we selected FLT3/ITD AML samples and injected them to NSG-SGM3 mice. We found that in a subset of these samples, dasatinib significantly inhibited LSCs engraftment. This subset of FLT3/ITD AML samples expressed higher levels of LYN, HCK,FGR and SRC as compared to the FLT3/ITD samples that were not sensitive to dasatinib therapy in vivo. In summary, we identified a subgroup of AML patients sensitive to dasatinib, based on mutational and expression profiles. Dasatinib has anti-leukemic effects on both blasts and LSCs. Further clinical studies are needed to demonstrate whether selection of tyrosine kinase inhibitors, based on specific biomarkers, could indeed prevent relapse. Disclosures Tavor: Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS companies: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Hsa_circ_0001947 suppresses acute myeloid leukemia progression by sponging hsa-miR-329-5p and regulating CREBRF expression

2019 ◽  
Author(s):  
Fengjiao Han ◽  
Chaoqin Zhong ◽  
Wei Li ◽  
Ruiqing Wang ◽  
Chen Zhang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Drug Resistance ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chromosomal Rearrangements ◽  
Gene Mutations ◽  
In Vivo Studies ◽  
Circular Rnas ◽  
Acute Myeloid

AbstractAcute myeloid leukemia (AML) is a heterogeneous group of diseases resulting from clonal transformation of hematopoietic precursors through the acquisition of chromosomal rearrangements and multiple gene mutations. Accumulating evidence has indicated that aberrantly expressed circular RNAs (circRNAs) are involved in cancer development and progression. However, their clinical values and biological roles in AML remain unclear. In this study, we identified the aberrantly down-regulated profile of hsa_circ_0001947 in AML through microarray analysis and validated it with quantitative reverse transcription polymerase chain reaction (qRT-PCR). Then, we explored the clinical significance, biological functions and regulatory mechanisms of hsa_circ_0001947 in AML patients. The results showed that lower hsa_circ_0001947 expression was positively correlated with higher leukemia cells in bone marrow or peripheral blood, indicating poor prognosis. Further, bioinformatics analysis demonstrated hsa_circ_0001947-hsa-miR-329-5p-CREBRF network. Down-regulation of hsa_circ_0001947 by siRNA promoted cell proliferation, inhibited apoptosis, reduced drug resistance of AML cells, and also decreased the expression of its targeted gene, CREBRF. The mimics of hsa-miR-329-5p reduced drug resistance and decreased the expression of CREBRF, while its inhibitor manifested anti-leukemia effects and increased CREBRF expression. In vivo studies revealed that silencing hsa_circ_0001947 promoted the tumor growth in BALB/c nude mice. Collectively, our findings suggest that hsa_circ_0001947 functions as a tumor inhibitor to suppress AML cell proliferation through hsa-miR-329-5p/CREBRF axis, which would be a novel target for AML therapy.

Drug-Response Signature Predicts Outcome in Adult Acute Myeloid Leukemia and Associates Poor Response with Molecular Characteristics of Hematopoietic Stem Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2024-2024
Author(s):  
Michael Heuser ◽  
Luzie U. Wingen ◽  
Doris Steinemann ◽  
Gunnar Cario ◽  
Nils von Neuhoff ◽  
...  
Keyword(s):  
Gene Expression ◽  
Drug Resistance ◽  
Acute Myeloid Leukemia ◽  
Progenitor Cells ◽  
Gene Expression Profile ◽  
Myeloid Leukemia ◽  
Drug Response ◽  
Poor Response ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Abstract Resistance to induction chemotherapy is of independent prognostic value in acute myeloid leukemia (AML). DNA microarrays were used to determine the gene-expression profile of AML blasts in 38 patients with good or poor response to induction chemotherapy. We selected an 11-sample training set, applying prediction analysis of microarrays (PAM) to devise a drug-response predictor which was tested on the remaining 27 samples and an independent set of samples recently published (Bullinger et al. 2004). Our drug-response predictor with 46 clones divided the 27 samples into two prognostic subgroups, the poor response group having a significantly shorter overall survival (P= .021). A subset of these 46 clones was sufficient to divide the published 62-sample test-set with intermediate risk cytogenetics into prognostically relevant subgroups (P= .028), adding prognostic information to that of known risk factors in multivariate analysis (hazard ratio, 2.8; 95 percent confidence interval, 1.4 to 5.8; P= .005). Thirteen of 39 drug resistance-enriched genes are known to be upregulated in hematopoietic stem/progenitor cells, and the expression pattern in normal CD34+ cells is highly correlated to the drug-resistance signature. This suggests that drug resistant AMLs show molecular features of hematopoietic stem/progenitor cells and can be identified by a characteristic gene-expression profile.

scholarly journals CD9 Defines Acute Myeloid Leukemia Stem Cells and is Regulated by Alpha-2-Macroglobulin

2020 ◽  
Author(s):  
Yongliang Liu ◽  
Guiqin Wang ◽  
Jiasi Zhang ◽  
Xue Chen ◽  
Huailong Xu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Drug Resistance ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Leukemia Stem Cells ◽  
Hematopoietic Stem ◽  
Therapy Strategy ◽  
And Migration ◽  
Acute Myeloid

Abstract Background: Leukemia stem cells (LSCs) are responsible for the initiation, progress and relapse of acute myeloid leukemia (AML). Therefore, the therapy strategy of targeting LSCs is hopeful to eradicate AML. In this study, we aim to identify LSC-specific surface markers and uncover the underlying mechanism of AML LSCs.Methods: Microarray gene expression data were used to investigate the candidate AML-LSC specific markers. CD9 expression was evaluated by flow cytometry in AML cell lines, patients with AML and normal donors. The biological characteristics of CD9-positive (CD9+) cells were analyzed by in vitro proliferation, chemotherapeutic drug resistance, migration and in vivo xenotransplantation assays. The molecular mechanism involved in CD9+ cell function was investigated by gene expression profiling. Effect of alpha-2-macroglobulin (A2M) on CD9+ cells was analyzed by proliferation, drug resistance and migration assays.Results: CD9 as a cell surface protein was specifically expressed on AML LSCs, but almost not expressed on normal hematopoietic stem cells (HSCs). CD9+ cells exhibited more resistance to chemotherapy drugs and higher migration potential than CD9-negative (CD9-) cells. More importantly, CD9+ cells possess the ability to reconstitute human AML in immunocompromised mice and promote tumor growth, suggesting CD9+ cells define the LSC population. Furthermore, we identified A2M plays a crucial role in CD9+ LSCs stemness maintenance. Down-regulation of A2M impairs drug-resistance and migration of CD9+ cells.Conclusion: Our findings suggest that CD9 is a new biomarker of AML LSCs and may serve as a promising therapeutic target.

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