miRNAs, Immune Signaling, and Myelodysplastic Syndromes Pathogenesis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. SCI-23-SCI-23
Author(s):  
Aly Karsan
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndromes ◽  
Myeloid Leukemia ◽  
Adaptor Protein ◽  
Innate Immune ◽  
Low Risk ◽  
Immune Signaling ◽  
Innate Immune Signaling ◽  
The Impact ◽  
Acute Myeloid

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell hematologic malignancies characterized by cytopenias as a result of ineffective hematopoiesis and a propensity to progress to acute myeloid leukemia. In low-risk MDS, a characteristic finding in the bone marrow is that of increased apoptosis. The most common structural genomic aberration observed in MDS is the interstitial deletion of the long arm of chromosome 5. MDS with isolated del(5q) is a subtype of MDS characterized by severe anemia and variable neutropenia, but normal or high platelet counts with dysplastic megakaryocytes. MicroRNAs (miRNAs) are short noncoding RNAs capable of exerting their effects by postranscriptionally regulating numerous mRNA targets. We have shown that deletion of chromosome 5q correlates with loss miR-145 and miR-146a that are abundant in hematopoietic stem/progenitor cells (HSPC). Genes involved in innate immune signaling are significantly overrepresented when predicted targets of these two miRNas are surveyed. Specifically, Toll-interleukin-1 receptor domain-containing adaptor protein (TIRAP) and tumor necrosis factor receptor-associated factor-6 (TRAF6) are targets of miR-145 and miR-16a, respectively. Knockdown of miR-145 and miR-146a together or enforced expression of TRAF6, to activate innate immune signaling in mouse HSPC, results in thrombocytosis, mild neutropenia and megakaryocytic dysplasia. A subset of mice transplanted with TRAF6-expressing marrow, in order to aberrantly activate innate immune signaling, progress either to marrow failure or acute myeloid leukemia. Loss of these miRNAs and consequent inappropriate immune signaling results in suppression of HSPC with a relatively greater effect on normal HSPC. Thus, inappropriate activation of innate immune signaling in HSPC phenocopies several general clinical features of low-risk MDS and of del(5q) MDS in particular. Recent work from our group defines additional cytokine pathways that are dysregulated by loss of miR-143 and miR-145. The impact of cytokine dysregulation on HSPC and the marrow microenvironment will be discussed. Disclosures Karsan: Celgene: Research Funding.

scholarly journals Functional Classification of TP53 Mutations in Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2725-2725
Author(s):  
Sayantanee Dutta ◽  
Gudrun Pregartner ◽  
Frank G. Rücker ◽  
Ellen Heitzer ◽  
Armin Zebisch ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Scoring Systems ◽  
Advisory Board ◽  
Low Risk ◽  
Missense Mutations ◽  
Tp53 Mutations ◽  
The Impact ◽  
Acute Myeloid

In more than 50% of human cancers, somatically acquired aberrations of the tumor suppressor gene TP53 are encountered. Approx. 10% of patients with acute myeloid leukemia (AML) reveal TP53 mutations with higher incidences in therapy-related subtypes and erythroleukemias. These mutations are regarded early events of leukemogenesis. In contrast to mere deletions at the TP53 locus, TP53 mutations confer an exceedingly adverse prognosis in AML even when occurring at a subclonal level. However whether different TP53 mutations in AML exhibit a different functional impact on disease progression or outcome remains unknown. In the present study, we have investigated this issue using four TP53 specific, functional scoring systems in a large cohort of patients of the German-Austrian AML study group (AMLSG). The AMLSG cohort consisted of a total of 1537 patients with newly diagnosed AML who were intensively treated within three multicenter, clinical trials. A total of 108 TP53 mutations were detected in 98 patients using targeted amplicon sequencing - 88 (81.4%) missense, 8 (7.4%) nonsense and 6 (5.6%) splice site mutations as well as 6 small insertions and deletions. For each of the four functional TP53 scores, we have assessed their impact on overall survival (OS) and event-free survival (EFS). First, we compared the impact of TP53 missense mutations in 84 patients with all other types of mutations (n= 14). In a next approach, TP53 mutations were grouped into disruptive (n=42) and non-disruptive (n=56) ones, based on the impact of the particular mutations on the protein structure predicted from the crystal structure of p53-DNA complexes (Poeta et al. New Engl J Med 2007). We then classified missense TP53 mutations (n=84) based on their "Evolutionary Action Scores (EAp53)" (Neskey et al. Cancer Res 2015). This algorithm takes evolutionary sensitivity and amino acid conservation into account and scores missense TP53 mutations from 0 to 100. Mutations with the high EAp53 score are considered high risk whereas wild type TP53 has an EAp53 score of zero. We extracted the EAp53 score of those AMLSG patients showing missense mutations from the respective server (http://mammoth.bcm.tmc.edu/EAp53) and used the threshold of 75 from the initial publication to divide the patients into low-risk (<75, n=49) and high-risk groups (≥75, n=35). However, with these three functional scoring systems, no difference regarding OS and EFS could be shown between the mutational groups. The "Relative Fitness Score (RFS)" was recently developed for the TP53 DNA binding domain (DBD) mutants as an indicator of their functional impact (Kotlar et al. Molecular Cell 2018). A catalogue of 9833 TP53 DBD mutants were generated and their selective growth was assessed in p53 null cancer cell lines. The RFS score for each mutant is the median of its relative enrichment or depletion in culture, calculated at 3 time points and depicted as a log (base 2) value. A high RFS indicates selective growth of the mutant corresponding to its higher fitness. We extracted the RFS for the TP53 DBD mutations of the AMLSG cohort (n=83) using the online data resource (GSE115072) and performed a receiver-operating characteristics (ROC) analysis to calculate the optimal threshold of RFS separating deceased from survivors most efficiently. Thereby, the best RFS cut-off value according to the Youden index was -0.135. Applying this threshold (low-risk RFS ≤ -0.135, n=25; high-risk RFS > -0.135, n= 58) we demonstrated a significantly better OS (P=0.009) and EFS (P=0.037) for patients with a low-risk RFS in multivariable analyses adjusting for age, white blood cell count, cytogenetics and type of AML. Using the AML-specific TP53 RFS score, we could show that more than 30% of patients with TP53 mutations (25/83) reveal a significantly better survival indicating that this score is of prognostic value. Based on these findings, we propose that - along with clinical parameters - RFS values of TP53 mutations should also be considered for a comprehensive risk assessment of TP53 mutated AML patients. Disclosures Zebisch: Celgene: Honoraria; Novartis: Honoraria, Other: Advisory board; AbbVie: Other: Advisory board; Roche: Honoraria. Bullinger:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Daiichi Sankyo: Honoraria; Gilead: Honoraria; Hexal: Honoraria; Menarini: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria; Seattle Genetics: Honoraria; Bayer: Other: Financing of scientific research; Abbvie: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria. Döhner:Daiichi: Honoraria; Jazz: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria; CTI Biopharma: Consultancy, Honoraria. Sill:Novartis: Other: Advisory board; AbbVie: Other: Advisory board; Astellas: Other: Advisory board; Astex: Other: Advisory board.

Remission Rates In Childhood Acute Myeloid Leukemia (AML) Utilizing a Dose-Intensive Induction Regimen with or without Gemtuzumab Ozogamicin (GO): Initial Results From the Children's Oncology Group Phase III Trial, AAML0531

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 182-182 ◽  
Author(s):  
Alan S Gamis ◽  
Todd A Alonzo ◽  
Robert B Gerbing ◽  
Richard Aplenc ◽  
Lillian Sung ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Low Risk ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Diagnostic Characteristics ◽  
Significant Difference ◽  
The Impact ◽  
Acute Myeloid

Abstract Abstract 182 Acute Myeloid Leukemia - Therapy, excluding Transplantation: Pediatric and Adult AML Therapy Therapy for childhood AML has evolved in North America over the past decade by pursuing a dose-intensive rather than an intensive-timing strategy. COG AAML0531 was a recently completed Phase III trial that was based upon the MRC AML 12 dose-intensive regimen which reported a complete remission (CR) rate of 93% in their ADE arm with 3% induction (Ind) deaths (Gibson, Blood 100:35a, 2002). While survival outcomes remain “blinded” as the last patients (pts) complete therapy, remission (REM) outcomes can now be examined. Utilizing a data cutoff of March 31, 2010, 1009 non-M3 AML pts were enrolled and after excluding 36 ineligible and 5 DS pts 968 eligible de novo AML were examined. Pts were randomized to standard therapy with or without GO at 3 mg/m2 given on Ind I day 6 and intensification II day 7. Induction consisted of 2 therapy courses (Ind I: ADE10 & Ind II: ADE8), cytarabine 100 mg/m2/dose bid × 10 days (8 days for Ind II), etoposide 100 mg/m2/day on days 1–5, and daunomycin 50 mg/m2/day on days 1–3-5. Pts remained on the trial regardless of REM status after Ind I; however pts not in CR after Ind II were taken off protocol. There were 968 pts that began Ind I and 851 pts that began Ind II, with 25 & 7 withdrawals, 50 & 29 who were still in Ind or had not yet submitted data, and 19 & 4 deaths in each course, respectively. CR (defined in the protocol as <5% morphologic blasts (blasts) & extramedullary disease (EMD) resolved) was achieved in 70% (628/900) & 86% (731/854) by the end of each Ind course, respectively. This is similar to that seen in the intensively-timed CCG-2961 after 2 Ind courses. The impact of REM status after Ind I upon CR rates after Ind II was then assessed. After Ind I (ADE10), partial REM (PR) (5-15% blasts) was seen in 12% (104/900) and persistent disease (PD) (>15% blasts) was seen in 14% (126/900) of whom 81% (79/98) & 60% (65/109) entered CR after Ind II (ADE8), respectively. The extent of PD after Ind I and its impact upon CR after Ind II was then examined. For those whose PD was defined by only residual EMD and whose marrow was in PR or CR, 97% achieved a CR after Ind II. For those whose PD was defined by marrow blasts >15%, 42% achieved CR following Ind II. We examined whether the degree of marrow disease (15-30% vs >30% blasts) impacted CR in the PD pts but found no significant difference in CR by amount of PD (52% vs 36%, p=.234). Among the 25 pts who withdrew from Ind I, response after Ind I was assessable in 19 (4 CR, 1 PR, 14 PD) although no impact upon Ind II outcome could be ascertained. Diagnostic characteristics were analyzed for CR rate after Ind II with selected risk factors listed in the table. Significant prognostic factors for REM after 2 courses were found by univariate analysis to include WBC>100,000 (OR=2.7, p<.001), FLT3-ITD (OR=2.9, p<.001), low risk cytogenetics (OR=0.2, p<.001). In a multivariate model in 464 pts who had all three risk factors reported to date, the same risk factors were independently predictive of outcome: WBC (OR=2.5, p=.002), FLT3-ITD (OR = 2.0, p=.034), and low risk cytogenetics (OR = 0.24, p=.007). FLT3 analysis for this abstract includes only those clinically available (after a trial amendment in the 3rd year). This will be updated with the FLT3 research sample analyses for those pts enrolled prior to the amendment. Overall toxic mortality by the end of Ind II of 2.7% (2.1% in ADE10, and 0.5% in ADE8) are similar to reported outcomes in the COG pilot trial, AAML03P1, (2.6%) and better than that seen in CCG-2961 (14.1% & 10%, pre-& post-amendment). These data provide an important background for the next COG Phase III trial utilizing this same standard Ind due to open soon and provides a platform for an early comparison between outcomes of the MRC trials and those in COG with identical Ind courses. Disclosures: Smith: Pfizer, Inc: Member, Medical Advisory Committee (for bosutinib—not GO).

AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations

Blood ◽  
2009 ◽  
Vol 114 (26) ◽  
pp. 5352-5361 ◽  
Author(s):  
Jih-Luh Tang ◽  
Hsin-An Hou ◽  
Chien-Yuan Chen ◽  
Chieh-Yu Liu ◽  
Wen-Chien Chou ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Remission Rate ◽  
Adult Patients ◽  
Poor Prognostic Factor ◽  
The Impact ◽  
Runx1 Mutation ◽  
Acute Myeloid

AbstractSomatic mutation of the AML1/RUNX1(RUNX1) gene is seen in acute myeloid leukemia (AML) M0 subtype and in AML transformed from myelodysplastic syndrome, but the impact of this gene mutation on survival in AML patients remains unclear. In this study, we sought to determine the clinical implications of RUNX1 mutations in 470 adult patients with de novo non-M3 AML. Sixty-three distinct RUNX1 mutations were identified in 62 persons (13.2%); 32 were in N-terminal and 31, C-terminal. The RUNX1 mutation was closely associated with male sex, older age, lower lactic dehydrogenase value, French-American-British M0/M1 subtypes, and expression of HLA-DR and CD34, but inversely correlated with CD33, CD15, CD19, and CD56 expression. Furthermore, the mutation was positively associated with MLL/PTD but negatively associated with CEBPA and NPM1 mutations. AML patients with RUNX1 mutations had a significantly lower complete remission rate and shorter disease-free and overall survival than those without the mutation. Multivariate analysis demonstrated that RUNX1 mutation was an independent poor prognostic factor for overall survival. Sequential analysis in 133 patients revealed that none acquired novel RUNX1 mutations during clinical courses. Our findings provide evidence that RUNX1 mutations are associated with distinct biologic and clinical characteristics and poor prognosis in patients with de novo AML.

scholarly journals Altered Spatial Composition of the Immune Cell Repertoire in Association to CD34+ Blasts in Myelodysplastic Syndromes and Secondary Acute Myeloid Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 186
Author(s):  
Marcus Bauer ◽  
Christoforos Vaxevanis ◽  
Haifa Kathrin Al-Ali ◽  
Nadja Jaekel ◽  
Christin Le Hoa Naumann ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndromes ◽  
Myeloid Leukemia ◽  
Multispectral Imaging ◽  
Immune Cell ◽  
Genetic Alterations ◽  
Spatial Proximity ◽  
Secondary Acute Myeloid Leukemia ◽  
Acute Myeloid

Background: Myelodysplastic syndromes (MDS) are caused by a stem cell failure and often include a dysfunction of the immune system. However, the relationship between spatial immune cell distribution within the bone marrow (BM), in relation to genetic features and the course of disease has not been analyzed in detail. Methods: Histotopography of immune cell subpopulations and their spatial distribution to CD34+ hematopoietic cells was determined by multispectral imaging (MSI) in 147 BM biopsies (BMB) from patients with MDS, secondary acute myeloid leukemia (sAML), and controls. Results: In MDS and sAML samples, a high inter-tumoral immune cell heterogeneity in spatial proximity to CD34+ blasts was found that was independent of genetic alterations, but correlated to blast counts. In controls, no CD8+ and FOXP3+ T cells and only single MUM1p+ B/plasma cells were detected in an area of ≤10 μm to CD34+ HSPC. Conclusions: CD8+ and FOXP3+ T cells are regularly seen in the 10 μm area around CD34+ blasts in MDS/sAML regardless of the course of the disease but lack in the surrounding of CD34+ HSPC in control samples. In addition, the frequencies of immune cell subsets in MDS and sAML BMB differ when compared to control BMB providing novel insights in immune deregulation.

scholarly journals Post-transplantation cyclophosphamide reduces the incidence of acute graft-versus-host disease in patients with acute myeloid leukemia/myelodysplastic syndromes who receive immune checkpoint inhibitors after allogeneic hematopoietic stem cell transplantation

2021 ◽  
Vol 9 (2) ◽  
pp. e001818 ◽  
Author(s):  
Chantal Saberian ◽  
Noha Abdel-Wahab ◽  
Ala Abudayyeh ◽  
Hind Rafei ◽  
Jacinth Joseph ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myelodysplastic Syndromes ◽  
Myeloid Leukemia ◽  
Acute Gvhd ◽  
Checkpoint Inhibitors ◽  
Post Transplantation ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Acute Myeloid

BackgroundImmune checkpoint inhibitors (ICIs) are being used after allogeneic hematopoietic stem cell transplantation (alloHCT) to reverse immune dysfunction. However, a major concern for the use of ICIs after alloHCT is the increased risk of graft-versus-host disease (GVHD). We analyzed the association between GVHD prophylaxis and frequency of GVHD in patients who had received ICI therapy after alloHCT.MethodsA retrospective study was performed in 21 patients with acute myeloid leukemia (n=16) or myelodysplastic syndromes (n=5) who were treated with antiprogrammed cell death protein 1 (16 patients) or anticytotoxic T lymphocyte-associated antigen 4 (5 patients) therapy for disease relapse after alloHCT. Associations between the type of GVHD prophylaxis and incidence of GVHD were analyzed.ResultsFour patients (19%) developed acute GVHD. The incidence of acute GVHD was associated only with the type of post-transplantation GVHD prophylaxis; none of the other variables included (stem cell source, donor type, age at alloHCT, conditioning regimen and prior history of GVHD) were associated with the frequency of acute GVHD. Twelve patients received post-transplantation cyclophosphamide (PTCy) for GVHD prophylaxis. Patients who received PTCy had a significantly shorter median time to initiation of ICI therapy after alloHCT compared with patients who did not receive PTCy (median 5.1 months compared with 26.6 months). Despite early ICI therapy initiation, patients who received PTCy had a lower observed cumulative incidence of grades 2–4 acute GVHD compared with patients who did not receive PTCy (16% compared with 22%; p=0.7). After controlling for comorbidities and time from alloHCT to ICI therapy initiation, the analysis showed that PTCy was associated with a 90% reduced risk of acute GVHD (HR 0.1, 95% CI 0.02 to 0.6, p=0.01).ConclusionsICI therapy for relapsed acute myeloid leukemia/myelodysplastic syndromes after alloHCT may be a safe and feasible option. PTCy appears to decrease the incidence of acute GVHD in this cohort of patients.

scholarly journals Actin cytoskeleton deregulation confers midostaurin resistance in FLT3-mutant acute myeloid leukemia

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Andoni Garitano-Trojaola ◽  
Ana Sancho ◽  
Ralph Götz ◽  
Patrick Eiring ◽  
Susanne Walz ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Actin Cytoskeleton ◽  
Myeloid Leukemia ◽  
Actin Polymerization ◽  
Cell Stiffness ◽  
Adhesion Forces ◽  
Frequent Mutations ◽  
New Perspective ◽  
The Impact ◽  
Acute Myeloid

AbstractThe presence of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) is one of the most frequent mutations in acute myeloid leukemia (AML) and is associated with an unfavorable prognosis. FLT3 inhibitors, such as midostaurin, are used clinically but fail to entirely eradicate FLT3-ITD + AML. This study introduces a new perspective and highlights the impact of RAC1-dependent actin cytoskeleton remodeling on resistance to midostaurin in AML. RAC1 hyperactivation leads resistance via hyperphosphorylation of the positive regulator of actin polymerization N-WASP and antiapoptotic BCL-2. RAC1/N-WASP, through ARP2/3 complex activation, increases the number of actin filaments, cell stiffness and adhesion forces to mesenchymal stromal cells (MSCs) being identified as a biomarker of resistance. Midostaurin resistance can be overcome by a combination of midostaruin, the BCL-2 inhibitor venetoclax and the RAC1 inhibitor Eht1864 in midostaurin-resistant AML cell lines and primary samples, providing the first evidence of a potential new treatment approach to eradicate FLT3-ITD + AML.

Sign in / Sign up

Export Citation Format

Share Document