scholarly journals Clinical Significance of ABCB1 in Acute Myeloid Leukemia: A Comprehensive Study

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1323 ◽  
Author(s):  
Boyer ◽  
Gonzales ◽  
Barthélémy ◽  
Marceau-Renaut ◽  
Peyrouze ◽  
...  
Keyword(s):  
Gene Expression ◽  
Drug Resistance ◽  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Ex Vivo ◽  
Standard Chemotherapy ◽  
Poor Prognostic Factor ◽  
Transporter Family ◽  
Acute Myeloid

ABCB1 is a member of the ATP binding cassette transporter family and high ABCB1 activity is considered as a poor prognostic factor in acute myeloid leukemia (AML) treated with intensive chemotherapy, its direct relation with drug resistance remains unclear. We evaluated ABCB1 activity in relation with clinical parameters and treatment response to standard chemotherapy in 321 patients with de novo AML. We assessed multiple clinical relationships of ABCB1 activity—ex vivo drug resistance, gene expression, and the ABCB1 inhibitor quinine were evaluated. ABCB1 activity was observed in 58% of AML and was linked to low white blood cell count, high expression of CD34, absence of FLT3-ITD, and absence of mutant NPM1. Moreover, ABCB1 activity was associated with worse overall- and event-free survival. However, ABCB1 activity did not directly lead to ex vivo drug resistance to anthracyclines. We found that ABCB1 was highly correlated with gene expressions of BAALC, CD34, CD200, and CD7, indicating that ABCB1 expression maybe a passenger characteristic of high-risk AML. Furthermore, ABCB1 was inversely correlated to HOX cluster genes and CD33. Thus, low ABCB1 AML patients benefited specifically from anti-CD33 treatment by gemtuzumab ozogamicin in addition to standard chemotherapy. We showed prognostic importance of ABCB1 gene expression, protein expression, and activity. Furthermore, ABCB1 was not directly linked to drug resistance, ABCB1 inhibition did not improve outcome of high ABCB1 AML patients and thus high ABCB1 may represent a passenger characteristic of high-risk AML.

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.

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.

Benefit of Anti-Infectious Prophylaxis in Patients with Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome Receiving Frontline “Targeted Therapy”.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2858-2858 ◽  
Author(s):  
Nitin Jain ◽  
Gloria N. Mattiuzzi ◽  
Jorge Cortes ◽  
Jennifer Cassat ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Targeted Therapy ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Fungal Infections ◽  
Antifungal Prophylaxis ◽  
Intensive Chemotherapy ◽  
Standard Chemotherapy ◽  
Antibacterial And Antifungal ◽  
Acute Myeloid

Abstract Background Patients with high risk (HR) myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) have significant toxicities such as mucositis, protracted neutropenia and severe infections when treated with standard chemotherapy. This had led to the development of ‘less intense’ chemotherapy (targeted therapy, TT). These treatments are expected to produce less toxicities, especially less immunosuppression. Antibiotic and antifungal prophylaxis are routinely given to patients undergoing intensive chemotherapy. It is not clear if the same strategy should be used for patients receiving less intensive chemotherapy. The objective of this study is to evaluate the outcome of patients receiving TT according to the use of antimicrobial prophylaxis. Methods We retrospectively reviewed the medical records of patients with AML and HR MDS that received TT as induction therapy from January 2000 to July 2007 at our institution. Baseline characteristics and antibiotic usage was recorded. All courses of TT received from start of therapy until outcome (response or failure) was assessed were evaluated, and infections or death occurring during any of these courses constituted an event. Results 225 patients received TT [decitabine or azacitidine n = 137 (61%); miscellaneous (tipifarnib, PKC412, imatinib, SAHA, and others) n=88 (39%)] for a total of 583 courses (median course per patient = 2). Median age was 72 years (range 13–89), 60% were male, 95% had Zubroad performance status ≤ 2 and 28% were neutropenic at the start of TT. None of the patients were placed in HEPA-filtered rooms (‘protected environment’) at any time. Each course of therapy was grouped into 1 of 4 groups based on the strategy use for infectious prophylaxis (table 1). Clinically documented infections and FUO were the most frequent type of infection reported in all the groups, followed by bacterial infections. Fungal infections were infrequent (total 5; group 1 = 1; group 2 = 2, group 3 = 2). There was no significant difference in the number of infectious episodes per course between the groups that received both antibacterial and antifungal prophylaxis vs. those who received no prophylaxis (p= 0.984). However, mortality was significantly higher during courses of TT administered without prophylaxis (p= 0.005). Conclusions As opposed to standard chemotherapy, fungal infections are infrequent in the patients treated with TT. Mortality is significantly higher in patients who did not receive any anti-microbial prophylaxis. The use of antibacterial and antifungal prophylaxis should be considered in patients receiving TT. Table 1: Groups based on antimicrobial strategy Strategy Strategy No. of courses No. of infectious episodes (%) No. of death (%) * p=0.984; # p=0.005 No prophylaxis 202 45 (22%) * 12 (5.94%) # Both bacterial and fungal prophylaxis 171 38 (18%) * 1 (0.58%) # Only bacterial prophylaxis 206 31 (15%) 6 (2.91%) Only fungal prophylaxis 4 0 (0%) 0 (0%)

Fludarabine and cytosine are less effective than standard ADE chemotherapy in high-risk acute myeloid leukemia, and addition of G-CSF and ATRA are not beneficial: results of the MRC AML-HR randomized trial

Blood ◽  
2006 ◽  
Vol 107 (12) ◽  
pp. 4614-4622 ◽  
Author(s):  
Donald W. Milligan ◽  
Keith Wheatley ◽  
Timothy Littlewood ◽  
Jenny I. O. Craig ◽  
Alan K. Burnett ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Relapse Rate ◽  
Myeloid Leukemia ◽  
Remission Rate ◽  
Disease Free Survival ◽  
High Dose ◽  
Standard Chemotherapy ◽  
All Trans Retinoic Acid ◽  
Acute Myeloid

AbstractThe optimum chemotherapy schedule for reinduction of patients with high-risk acute myeloid leukemia (relapsed, resistant/refractory, or adverse genetic disease) is uncertain. The MRC AML (Medical Research Council Acute Myeloid Leukemia) Working Group designed a trial comparing fludarabine and high-dose cytosine (FLA) with standard chemotherapy comprising cytosine arabinoside, daunorubicin, and etoposide (ADE). Patients were also randomly assigned to receive filgrastim (G-CSF) from day 0 until neutrophil count was greater than 0.5 × 109/L (or for a maximum of 28 days) and all-trans retinoic acid (ATRA) for 90 days. Between 1998 and 2003, 405 patients were entered: 250 were randomly assigned between FLA and ADE; 356 to G-CSF versus no G-CSF; 362 to ATRA versus no ATRA. The complete remission rate was 61% with 4-year disease-free survival of 29%. There were no significant differences in the CR rate, deaths in CR, relapse rate, or DFS between ADE and FLA, although survival at 4 years was worse with FLA (16% versus 27%, P = .05). Neither the addition of ATRA nor G-CSF demonstrated any differences in the CR rate, relapse rate, DFS, or overall survival between the groups. In conclusion these findings indicate that FLA may be inferior to standard chemotherapy in high-risk AML and that the outcome is not improved with the addition of either G-CSF or ATRA.

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.

scholarly journals Development and validation of a novel survival model for acute myeloid leukemia based on autophagy-related genes

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11968
Author(s):  
Li Huang ◽  
Lier Lin ◽  
Xiangjun Fu ◽  
Can Meng
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Tumor Growth ◽  
Risk Score ◽  
Myeloid Leukemia ◽  
Low Risk ◽  
Tumor Cell Death ◽  
Score Model ◽  
Acute Myeloid

Background Acute myeloid leukemia (AML) is one of the most common blood cancers, and is characterized by impaired hematopoietic function and bone marrow (BM) failure. Under normal circumstances, autophagy may suppress tumorigenesis, however under the stressful conditions of late stage tumor growth autophagy actually protects tumor cells, so inhibiting autophagy in these cases also inhibits tumor growth and promotes tumor cell death. Methods AML gene expression profile data and corresponding clinical data were obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, from which prognostic-related genes were screened to construct a risk score model through LASSO and univariate and multivariate Cox analyses. Then the model was verified in the TCGA cohort and GEO cohorts. In addition, we also analyzed the relationship between autophagy genes and immune infiltrating cells and therapeutic drugs. Results We built a model containing 10 autophagy-related genes to predict the survival of AML patients by dividing them into high- or low-risk subgroups. The high-risk subgroup was prone to a poorer prognosis in both the training TCGA-LAML cohort and the validation GSE37642 cohort. Univariate and multivariate Cox analysis revealed that the risk score of the autophagy model can be used as an independent prognostic factor. The high-risk subgroup had not only higher fractions of CD4 naïve T cell, NK cell activated, and resting mast cells but also higher expression of immune checkpoint genes CTLA4 and CD274. Last, we screened drug sensitivity between high- and low-risk subgroups. Conclusion The risk score model based on 10 autophagy-related genes can serve as an effective prognostic predictor for AML patients and may guide for patient stratification for immunotherapies and drugs.

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