scholarly journals Tobacco Use Predicts Unique Mutagenesis Signature in Acute Myelogenous Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1297-1297
Author(s):  
Tran Hoang ◽  
Gianfranco Bittar ◽  
Purnima Sravanti Teegavarapu ◽  
Martha P. Mims ◽  
Gustavo Rivero
Keyword(s):  
Lung Cancer ◽  
Stem Cell ◽  
Acute Myelogenous Leukemia ◽  
Research Funding ◽  
Myelogenous Leukemia ◽  
Smoking History ◽  
Hemopoietic Stem Cell ◽  
Smoking Exposure ◽  
Acute Myelogenous ◽  
Privately Held

Abstract Background: Endogenous and exogenous processes are active in leukemia initiation. Single-base substitution (SBS) data permits aggregation into mutational signatures [MS] with potential for clinical application. Acetaldehyde and Benzo [a] pyrene (BaP) are tobacco mutagens that "drive" signature SBS4 [Catalog of Somatic Mutations in Cancer (COSMIC) https://cancer.sanger.ac.uk/signatures/sbs/] in lung cancer characterized by C>A transversion. This specific MS is associated with favorable response to immune-checkpoint therapy (ICT). Previous epidemiologic data correlate smoking with cancer including leukemia. Tobacco mutagens are ubiquitously distributed in organs once inhaled. However, how mutagenicity develops in hemopoietic stem cell/progenitor is unknown. In this study, our primary objective was to investigate the incidence of MS among patients (pt) diagnosed with Acute Myelogenous Leukemia (AML) with smoking exposure. Methods: After IRB approval, we performed retrospective analysis using the BCM AML database. Data from 58 AML pt was available. For all analysis, current and past smoking were aggregated into "positive exposure". SBSs (C>A, C>G, C>T, T>C, T>G, G>C, G>A, GT and AG) in smokers and never smoker were annotated from ELN 2017 predefined subgroups [i.e. CEBPA, NPM1, P53, ASLX1, RUNX1 and FLT3ITD] and all additional mutations in individual pt. We used descriptive statistics to detect differential clinical predictors for smoking induced MS. Chi-square was used to determine association between SBSs and smoking history. Stepwise logistic regression allowed identification of independent MS that correlated with smoking. Results: Median age for 58 AML pt was 65.5 years [y] (range, 22-89) and 58.3% were male. Smokers were 26/58 (44.8%). Whites, African Americans, Hispanics and Asians comprised 35/60 (58.3%), 7/60 (7.1%), 16/60 (26.6%) and 2/60 (2.3%), respectively. 112 myeloid mutations [91 SBSs, 16 duplications, 16 deletions, and 3 insertions] were recorded. 32/58 (55.1%) had positive smoking exposure. Previous reports suggest that C>A [COSMIC=SBS4], G>C [COSMIC= SBS2 and SBS13] and T>C [COSMIC=SBS5] retain strong smoking association with cancer. However, in addition to C>A [HR=0.10 (0.01-0.6), p=0.02], our logistic model identified G>A, HR=0.12 (0.02-0.4), p=0.002, as predictors of exposure. C>A+G>A MS was observed in 19/25 (76%) of AML pt with smoking exposure, OR=6.56 (1.8-23.9), p=0.002. By ELN-2017 defined subgroups, P53, ASXL1, RUNX1, FLT3 and NPM1 mut were detected in 11/58 (18.9%), 5/58 (8.6%), 4/58 (6.8%), 13/58 (22.4%) and 5/58 (8.6%). RAS was seen in 12/58 (20.6%), IDH 12/58 (20.6%), DNMT3A 10/58 (17.2%) and TET2 7/58 (12%). Interestingly, among smokers exhibiting or not C>A+G>A SBP substitution, P53 was identified in 3/3 (100%) v 0/3 (0%), p=0.05 and RAS in 75% v 25%, p=0.08. Conclusions: Our data suggest that C>A and G>A SBS substitutions are frequently observed in AML pt with smoking exposure. Hemopoietic stem cell/progenitors exposed to smoking products may initiate similar SBSs substitutions as those observed in tobacco induced solid tumors. Previously, lung cancer studies demonstrated that TP53 and KRAS mutations tumors exhibited high rate of C>A transversion associated with tumor-infiltrating lymphocytes (TIL) and high program-death 1 ligand (PD-L1) expression. Further similar studies are needed in adult diagnosed with P53 AML. Figure 1 Figure 1. Disclosures Mims: IDEC: Current holder of individual stocks in a privately-held company; Biogen: Current holder of individual stocks in a privately-held company; Incyte: Research Funding; Pfizer: Research Funding; AVEO: Research Funding; Celgene: Research Funding.

A Role for IL1RAP in Acute Myelogenous Leukemia Stem Cells Following Treatment and Progression

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4266-4266 ◽  
Author(s):  
Tzu-Chieh Ho ◽  
Craig T Jordan ◽  
Mark W. LaMere ◽  
John M. Ashton ◽  
Kristen O'Dwyer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cell ◽  
Cell Lines ◽  
Small Molecule ◽  
Acute Myelogenous Leukemia ◽  
Research Funding ◽  
Myelogenous Leukemia ◽  
Molecule Inhibitor ◽  
Acute Myelogenous ◽  
Pre Treatment

Abstract Background Acute Myelogenous Leukemia (AML) evolves as many patients who are responsive to therapy upfront are resistant to the same agents when applied at relapse. We previously reported the results of our prospective efforts to formally assess the evolution of the leukemia stem cell (LSC) population(s) during patients' clinical courses. We identified a 9-90 fold increase in LSC activity and greatly increased phenotypic diversity of the LSC population. To identify the potential mechanisms underlying these changes we further characterized functionally-defined LSC populations from paired diagnosis and relapse samples. Methods Primary bone marrow and peripheral blood samples were collected on IRB approved protocols from patients with newly diagnosed AML undergoing induction therapy as well as normal donors. Twenty-five patients who relapsed after achieving a complete remission were selected for further study. Screening studies identified seven patients whose pre-therapy samples demonstrated sustained engraftment of NSG mice following transplantation. Transcriptional profiling of highly enriched LSC populations from seven patients was performed using ABI TaqMan® Low Density Array (TLDA) qPCR analyses following pre-amplification using a novel 153 gene expression platform. Protein expression levels of interleukin-1 receptor accessory protein (IL1RAP) on bulk leukemia cells and LSC populations from 25 patients were assessed by flow cytometry. The impact of loss of IL1RAP was assessed using lentiviral based shRNA targeting all IL1RAP isoforms followed by assessment of proliferation, apoptosis, colony forming unit (CFU) activity and NSG engraftment capacity in human cell lines as well as in primary patient samples. Downstream signaling events for IL1RAP were probed using a small molecule inhibitor approach. Results While the majority of the LSC populations' gene expression profile remained stable, twelve genes were differentially expressed between pre-treatment and relapsed LSC populations including IL1RAP. Flow cytometric analyses confirmed that IL1RAP is overexpressed on both bulk leukemia populations as well as LSC populations at diagnosis and relapse in comparison to normal hematopoietic stem cell (HSC) populations. Targeting ILRAP1 using shRNA in both cell lines and primary AML samples resulted in impaired proliferation, increased apoptosis, a marked loss of CFU capacity and impaired NSG engraftment. IL1 signaling is known to involve both the MAPkinase and NFKappB pathways. To determine which pathways are involved in IL1RAP mediated LSC survival, we performed a small molecule inhibitor screen targeting elements in both signaling cascades. Established inhibitors of the NFKappaB pathway resulted in loss in loss of leukemic cell function while MAPK signaling inhibition had minimal to no effect. Conclusions We identified IL1RAP as being overexpressed in both bulk leukemia and functionally defined LSC populations from pre-treatment and relapsed AML samples. Loss of IL1RAP was associated with a marked decline in LSC function. Preliminary studies support a primary role for the NF Kappa B pathway in LSC function. Our findings support a critical role for IL1RAP in LSC function and support its development as a target for AML therapy in both the upfront and relapse setting. Disclosures Wang: Immunogen: Research Funding. Calvi:Fate Therapeutics: Patents & Royalties. Becker:Millenium: Research Funding.

Marrow irradiation with high-dose 153Samarium-EDTMP followed by chemotherapy and hematopoietic stem cell infusion for acute myelogenous leukemia

2006 ◽  
Vol 47 (8) ◽  
pp. 1583-1592 ◽  
Author(s):  
Vilmarie Rodriguez ◽  
Peter M. Anderson ◽  
Mark R. Litzow ◽  
Linda Erlandson ◽  
Barbara A. Trotz ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Acute Myelogenous Leukemia ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Acute Myelogenous

scholarly journals Evolution Of Acute Myelogenous Leukemia Stem Cell Properties Following Treatment and Progression

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 883-883 ◽  
Author(s):  
TzuChieh Ho ◽  
Mark W LaMere ◽  
Kristen O'Dwyer ◽  
Jason H. Mendler ◽  
Jane L. Liesveld ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cell ◽  
Acute Myelogenous Leukemia ◽  
Cell Model ◽  
Phenotypic Diversity ◽  
Hierarchical Organization ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Leukemia Stem Cell ◽  
Acute Myelogenous

Abstract Acute Myelogenous Leukemia (AML) is a disease that clinically evolves over time as many patients who are responsive to therapy upfront acquire resistance to the same agents when applied in the relapse setting. The stem cell model for AML has been invoked to explain primary resistance to standard therapy; the leukemia stem cell (LSC) population representing a therapy-refractory reservoir for relapse. There have been no prospective efforts to formally assess the evolution of the LSC population during patients’ clinical course. We performed a prospective characterization of specimens from a well-defined cohort of patients with AML at diagnosis and relapse to assess the frequency and phenotype of functionally defined LSCs. Methods Primary bone marrow and peripheral blood samples were collected on IRB approved protocols from patients with newly diagnosed AML undergoing induction therapy. Twenty-five patients who relapsed after achieving a complete remission were selected for further study. Screening studies identified seven patients whose pre-therapy samples demonstrated sustained engraftment of NSG mice following transplantation. Pre-therapy and post-relapse LSC frequencies were assessed using xenotransplantation limiting dilution analyses (LDA). We assessed the frequencies of CD45RA, CD32, TIM-3, CD96, CD47, and CD97 expressing populations that have been previously published to possess LSC activity. Functionally validated pre-therapy and post-relapse LSC populations were identified using fluorescent labeled cell sorting and NSG xenotransplantation. LSC activity was confirmed for each population using secondary xenotransplantation. Gene expression analysis of highly enriched LSC populations from pre-therapy and post-relapse samples was performed using ABI TILDA qPCR analyses following pre-amplification. Results We demonstrated by LDA an 8 to 42-fold increase in LSC frequency between diagnosis and relapse in paired primary patient samples. The increase in LSC activity was not associated with an increase in frequency for phenotypically-defined populations previously reported to possess LSC activity. Rather, we found that LSC activity expanded at relapse to immunophenotypic populations of leukemic cells that did not possess LSC activity prior to treatment. Moreover, in all patients, the number of phenotypically distinct LSC populations (as defined by CD34 and CD38 or CD32 and CD38) detectable at relapse was dramatically expanded. Further, while the majority of the LSC populations’ gene expression profile remained stable between diagnosis and relapse, a subset of genes were enriched in defined LSC populations at relapse including IL3-receptor alpha and IL1-RAP, both previously demonstrated to play a role in LSC biology. Conclusions This study is the first to characterize the natural evolution of LSCs in vivo following treatment and relapse. We demonstrate an increase in LSC activity and greatly increased phenotypic diversity of the LSC population, suggesting a loss of hierarchical organization following relapse. These findings demonstrate that treatment of AML patients with conventional chemotherapy regimens can promote quantitative and qualitative expansion of the LSC compartment. Further, the data indicate that surface antigen immune-phenotype is not predictive of function in relapse and suggest a major limitation to efforts targeting specific surface antigens in the relapse setting. Understanding the mechanisms by which LSC expansion occurs and how to target it will likely improve our currently poor treatment options for patients who relapse. Disclosures: Becker: Millenium: Research Funding.

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