MicroRNA composition of plasma extracellular vesicles: a harbinger of late cardiotoxicity in long-term survivors of acute lymphoblastic leukemia treated with doxorubicin

Abstract The use of doxorubicin is associated with an increased risk of acute and long-term cardiomyopathy. Despite the constantly growing number of cancer survivors, little is known about the transcriptional mechanisms which progress in the time leading to a severe cardiac outcome. It is also unclear whether long-term transcriptomic alterations related to doxorubicin use are similar to transcriptomic patterns present in patients suffering from other cardiomyopathies. Here we have sequenced miRNA from total plasma and extracellular vesicles (EVs) from 66 childhood acute lymphoblastic leukemia survivors treated with doxorubicin and 61 healthy controls (254 samples in total). We analyzed processes regulated by differentially expressed miRNA and cross-validated our results with the data of patients with clinically manifested cardiomyopathies. Our analyses indicate that the circulating compartment used for inspection should be selected with particular attention. miRNAs contained within EVs may be particularly informative in terms of cardiomyopathy development and may regulate pathways related to neurotrophin, transforming growth factor beta or epidermal growth factor receptors (ErbB). Among miRNAs differentially expressed in vesicles, which additionally are also most variable between groups, we identified those correlated with echocardiographic parameters, including miR-144-3p and miR-423-3p and respectively for plasma miRNAs: let-7g-5p, miR-16-2-3p. Among these, vesicular miR-144-3p correlates with the highest number of echocardiographic parameters and is also differentially expressed in the circulation of patients with dilated cardiomyopathy. We also show that in ALL survivors' distribution of particular miRNAs, e.g., miR-184 between plasma and EVs is different than in healthy controls. This suggests persistent alterations within the cellular sorting and exporting system.

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Inflammatory Biomarkers after an Exercise Intervention in Acute Lymphoblastic Leukemia Survivors

10.21203/rs.3.rs-961004/v1 ◽

2021 ◽

Author(s):

Tuomas Lähteenmäki ◽

Liisa Järvelä ◽

Harri Niinikoski ◽

Anu Huurre ◽

Arja Harila-Saari

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Physical Exercise ◽

Exercise Intervention ◽

Lymphoblastic Leukemia ◽

Exercise Program ◽

Low Grade ◽

Healthy Controls ◽

Protein Levels ◽

Home Based ◽

Increased Risk

Abstract BackgroundCancer survivors show increased risk for non-communicable diseases and chronic low-grade inflammation characterizes the development of such diseases. We investigated inflammatory plasma protein profiles of survivors of acute lymphoblastic leukemia (ALL) in comparison to healthy controls and after an intervention with a home-based exercise program. ProcedureSurvivors of ALL aged 16-30 years (n=21) with a median time of 15.9 years from diagnosis, and sex- and age-matched healthy controls (n=21), were studied. Stored plasma samples were analyzed with Olink’s 92-protein-wide Inflammation panel in 21 ALL long-term survivors at baseline, after a 16-week home-based exercise intervention (n=17) and in 21 age- and sex-matched controls at baseline. Protein expression levels were compared between the groups. ResultsInflammatory protein levels did not differ between the survivors and controls at baseline. Significantly reduced levels after the intervention were found in 11 proteins related to either vascular inflammation, insulin resistance, or both: TNFSF14, OSM, MCP-1, MCP-2, FGF-21, CCL4, TGF-alpha, TRAIL, ADA, CXCL6, and LAP TGF-beta-1. ConclusionsThe ALL survivors were not significantly more affected by inflammation than controls at baseline. The survivors’ 16-week physical exercise intervention led to significant beneficial change in inflammation protein levels. Physical exercise should be promoted for survivors of cancer.

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NRF2-related transcriptomic alterations as a long-term effect of doxorubicin treatment for childhood acute lymphoblastic leukemia

10.21203/rs.3.rs-418155/v1 ◽

2021 ◽

Author(s):

Justyna Totoń-Żurańska ◽

Joanna Sulicka-Grodzicka ◽

Michal Seweryn ◽

Ewelina Pitera ◽

Przemyslaw Kapusta ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Epithelial To Mesenchymal Transition ◽

Lymphoblastic Leukemia ◽

Total Plasma ◽

Doxorubicin Treatment ◽

Mesenchymal Transition ◽

Acute Response ◽

Increased Risk

Abstract The use of doxorubicin is associated with an increased risk of acute and long-term cardiomyopathy. Despite that the number of cancer survivors is growing constantly, little is known about the transcriptional mechanisms which progress in time leading to severe cardiac outcome. It is also unclear whether long-term transcriptomic alterations are related to an acute response to doxorubicin. We have sequenced miRNA from total plasma and extracellular vesicles (EVs) from 66 acute lymphoblastic leukemia (ALL) survivors treated with doxorubicin and 61 healthy controls (254 samples in total). We identified 94 and 33 TFs regulating differentially expressed miRNA in plasma and EVs compartments, respectively. For total plasma we found: HEY1, NRF2, HIF1A, NOTCH1, and for EVs: TGFB, ZEB1, ASCL2, PELP1, SIP1, TWIST1. Analysis of the data from patients with dilated and idiopathic cardiomyopathy revealed similarities with our data from EVs, especially in the activity of TFs related to epithelial-to-mesenchymal transition (EMT). To verify if similarities exist between acute and long-term response to doxorubicin, we performed experiments on cultured as well as we studied the role of NRF2, previously considered as an important player in acute response, in transcriptomic network upon doxorubicin treatment). KEGG analysis of miRNA targets for EVs indicates development of cardiomyopathy, whereas among GO process we found terms related to cardiac septum. In vitro experiments revealed that NRF2 is co-regulated with NOTCH effectors from HEY family, with known role in muscle regeneration. NRF2 and doxorubicin treatment contribute also to the dysregulation of TWIST family, important for the process of EMT.

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Microsatellite Instability and Frameshift Mutations in BAX and Transforming Growth Factor-β RII Genes Are Very Uncommon in Acute Lymphoblastic Leukemia In Vivo But Not in Cell Lines

Blood ◽

10.1182/blood.v92.1.230.413k17_230_233 ◽

1998 ◽

Vol 92 (1) ◽

pp. 230-233 ◽

Cited By ~ 38

Author(s):

Jan J. Molenaar ◽

Bénédicte Gérard ◽

Cécile Chambon-Pautas ◽

Hélène Cavé ◽

Michel Duval ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Growth Factor ◽

Microsatellite Instability ◽

Cell Lines ◽

Transforming Growth Factor ◽

Lymphoblastic Leukemia ◽

Transforming Growth Factor Β ◽

Mononucleotide Repeat ◽

Frameshift Mutations ◽

Β Receptor

Mutations in the DNA mismatch repair (MMR) system lead to an instability of simple repetitive DNA sequences involved in several cancer types. This instability is reflected in a high mutation rate of microsatellites, and recent studies in colon cancer indicate that defects in MMR result in frequent frameshift mutations in mononucleotide repeats located in the coding regions of BAX and transforming growth factor-β (TGF-β) receptor genes. Circumstantial evidence suggests that the MMR defect may be involved in some lymphoid malignancies, although several allelotype analyses have concluded on the low level of microsatellite instability in acute lymphoblastic leukemias. To further evaluate the implication of MMR defects in leukemogenesis, we have studied a series of 98 children with acute lymphoblastic leukemia and 14 leukemic cell lines using several indicators of MMR defects. Microsatellite markers were compared between blast and normal DNA from the same patients and mutations were sought in mononucleotide repeat sequences of BAX and TGF-β receptor II (TGF-β RII). The absence of microsatellite instability (MI) and the absence of mutations in the genes examined from patient's leukemic cells contrasted with the observation that half of the cell lines displayed a high degree of MI and that three of seven of these mutator cell lines harbored mutations in BAX and/or TGF-β RII. From these results we conclude that MMR defects are very uncommon in freshly isolated blasts but are likely to be selected for during the establishment of cell lines.

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Rs4846049 Polymorphism at the 3′-UTR of MTHFR Gene: Association with Susceptibility to Childhood Acute Lymphoblastic Leukemia

BioMed Research International ◽

10.1155/2019/4631091 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12

Author(s):

Xiaolei Li ◽

Shunguo Zhang ◽

Feng Yu

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Mrna Expression ◽

Protective Factor ◽

Lymphoblastic Leukemia ◽

Childhood Acute Lymphoblastic Leukemia ◽

Allele Carrier ◽

Genotype Distribution ◽

Healthy Controls ◽

Mthfr Polymorphisms ◽

Increased Risk

Background. Accumulating evidence has suggested the polymorphisms of methylenetetrahydrofolate reductase (MTHFR) were associated with susceptibility to childhood acute lymphoblastic leukemia (ALL). However, the known conclusions of currently known polymorphic loci (677 C > T and 1298 A > C) remain controversial. This study was to investigate new genetic biomarkers for ALL by analyzing the MTHFR polymorphisms at the 3′-untranslated region, which is a location bound by miRNAs. Methods. Polymorphisms of rs4846049 (miR-555 binding) were assessed by PCR amplification and direct sequencing in 110 ALL patients and 105 healthy controls. The relative expression of MTHFR was detected by qRT-PCR. Results. Overall, genotype distribution or allele carrier frequencies were not significantly different between patients with ALL and healthy controls (P>0.05). Subgroup analysis results showed that T allele (OR = 0.134, 95% CI = 0.028–0.639; P=0.005) or genotypes with T allele (TT + GT) (OR = 0.133, 95% CI: 0.024–0.727; P=0.017) may be a protective factor for ALL susceptibility in patients with age >8 years. This conclusion was also true for the group only focusing on the precursor B-cell ALL patients. Furthermore, karyotype abnormality was more commonly observed in patients with the GG genotype (56.0%) compared to carriers of TT (0%) or GT (40.6%) genotypes, while c-myc break frequency was significantly higher in TT carriers (33%) than that of patients with GT (3.1%) or GG (0%) genotypes. PCR analysis showed patients carrying the GG genotype of rs4846049 exhibited the reduced mRNA expression of MTHFR. Conclusion. MTHFR rs4846049 polymorphism may be associated with increased risk of childhood with ALL and MTHFR mRNA expression.

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Reduced Neuroanatomic Volumes in Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.2012.47.4031 ◽

2013 ◽

Vol 31 (17) ◽

pp. 2078-2085 ◽

Cited By ~ 46

Author(s):

Bernward Zeller ◽

Christian K. Tamnes ◽

Adriani Kanellopoulos ◽

Inge K. Amlien ◽

Stein Andersson ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Gray Matter ◽

Lymphoblastic Leukemia ◽

Childhood Acute Lymphoblastic Leukemia ◽

Intracranial Volume ◽

Healthy Controls ◽

Childhood All ◽

Cortical Gray Matter ◽

Long Term Survivors

Purpose To compare regional brain volumes in adult long-term survivors of childhood acute lymphoblastic leukemia (ALL) and healthy controls. Patients and Methods We investigated 130 survivors of childhood ALL diagnosed between 1970 and 2002 with magnetic resonance imaging (MRI) and neuropsychological testing at a median of 22.5 years after diagnosis. Morphometric analyses including whole-brain segmentation were performed using a validated automated procedure; 130 healthy adults served as controls. Results Compared with healthy controls, ALL survivors showed significantly smaller volumes of cortical gray matter, cerebral white matter, amygdala, caudate, hippocampus, thalamus, and estimated intracranial volume. Effect sizes ranged from small to medium. The strongest effect was found for the caudate, which on average was 5.2% smaller in ALL survivors. Caudate volumes were also smaller when controlling for intracranial volume, suggesting a specific effect. Neither age at diagnosis nor treatment variables such as radiation therapy or drug dose had a major impact on neuroanatomic volumes. Neuropsychological assessment revealed reduced processing speed, executive function, and verbal learning/memory in survivors compared with controls but no difference in estimated general intellectual ability. In ALL survivors, but not in controls, neuropsychological test results correlated with volumes of cortical gray matter, caudate, and thalamus as well as intracranial volume. Conclusion Structural MRI of long-term survivors of childhood ALL demonstrated smaller volumes of multiple brain structures compared with healthy controls. Because of possible selection biases, these results must be interpreted with caution. Future studies are required to clarify the significance of these findings and the neurobiologic mechanisms involved.

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Late Effects of Acute Lymphoblastic Leukemia Therapy in Patients Diagnosed at 0-20 Years of Age

Hematology ◽

10.1182/asheducation-2011.1.238 ◽

2011 ◽

Vol 2011 (1) ◽

pp. 238-242 ◽

Cited By ~ 32

Author(s):

Leslie L. Robison

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Late Effects ◽

Lymphoblastic Leukemia ◽

Survival Rates ◽

Adverse Outcomes ◽

Number Of Children ◽

Second Neoplasms ◽

Increased Risk ◽

Late Morbidity

Abstract Survival rates for children with acute lymphoblastic leukemia (ALL) have increased dramatically over the past 4 decades, with 5-year survival rates of > 90% in recent trials. With the increasing number of children and adolescents cured of ALL, identifying and characterizing the occurrence of long-term adverse late effects has become increasingly important. In this young population, successful treatment of ALL is associated with increased risk of adverse outcomes such as late mortality, second neoplasms, chronic health conditions, endocrine dysfunction, and psychological function. Research efforts conducted through large survivor cohorts, such as the Childhood Cancer Survivor Study, are providing new and important insights into the very long-term consequences of ALL therapy, while providing direction for screening recommendations and intervention-based approaches for reducing late morbidity and mortality.

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Coagulation abnormalities in childhood acute lymphoblastic leukemia: assessing the impact of L-asparaginase therapy in Ghana

Thrombosis Journal ◽

10.1186/s12959-021-00297-4 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

William Osei-OWusu ◽

David Ofosu Ntiamoah ◽

Gordon Asare Akuffo ◽

Selina Mintaah ◽

Michael Owusu ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Protein S ◽

Childhood Acute Lymphoblastic Leukemia ◽

Induction Phase ◽

Healthy Controls ◽

Increased Risk ◽

Consolidation Phase ◽

The Impact ◽

Control Study

Abstract Background Although the rate of childhood acute lymphoblastic leukemia (ALL) is increasing in Africa, there is a dearth of information on the disease and the dynamics of hemostatic parameters with therapy. Methods In this case-control study, we evaluated variations in the level/activity of selected coagulation parameters among cALL in Ghana and healthy controls stratified by stage of therapeutic management. Results In all, the research recruited 104 participants comprising 26 cALL cases and 78 healthy controls. The cALL group had significantly higher prothrombin time (PT) (p = 0.001), activated partial thromboplastin time (APTT) (p < 0.0001) and D-dimers (p = 0.001) but lower platelet (PLT) count, protein C (PC) (p < 0.0001), protein S (PS) (p < 0.0001) and antithrombin III (ATIII) (p < 0.0001) compared to controls. Compared to the healthy controls, activity of PC was lower during induction (p < 0.0001), consolidation (p = 0.005) and maintenance phases of chemotherapy (p = 0.012) while activities of PS and ATIII were lower at both induction (p < 0.0001, p = 0.006) and consolidation (p < 0.0001, p = 0.018) phases of chemotherapy. Conclusion Our findings provide evidence in the context of Africa and corroborates previous reports that cALL could result in a state of hypercoagulability, possibly leading to a high risk of thrombosis and thromboembolic complications. This possibly increased risk is not limited to the induction phase but also the consolidation phase.

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