scholarly journals Molecular and Clinical Aspects of Acute Myeloid Leukemia with Inv(3)(q21q26)/t(3;3)(q21;q26) Carrying Spliceosomal Mutations

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 7-8
Author(s):  
Hassan Awada ◽  
Cassandra M Kerr ◽  
Heesun J. Rogers ◽  
Jaroslaw P. Maciejewski ◽  
Valeria Visconte
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Dominant Gene ◽  
Prognostic Significance ◽  
Genetic Alterations ◽  
Splicing Factor ◽  
Clinical Aspects ◽  
De Novo Aml ◽  
Acute Myeloid

Inversion or translocation of the chromosome 3, specifically inv(3)(q21q26.2/ t(3;3)(q21;q26.2) are present in 1-2% of acute myeloid leukemia (AML) cases and are classified as a distinct entity in the 2016 WHO classification. Hallmark genetic alterations in this entity include mutations in GATA2 and MECOM. In fact, these rearrangements result in over activation of MECOM due to juxtaposition with a distal GATA2 enhancer. Cytomorphologic phenotypes include anemia, normal to elevated platelets and multilineage dysplasia in a hyperplastic bone marrow (BM). Studies have shown the frequent occurrence of NF1, NRAS and RUNX1 mutations. While proceeding towards our molecularly informed AML subtyping (Awada, Blood 2019;1406), we observed a high occurrence of somatic mutations in the splicing factor SF3B1 in inv(3)/t(3;3) AML. We were particularly intrigued by this observation considering several key aspects of SF3B1 mutations in the context of MDS. For instance, SF3B1 mutations are highly associated with clear phenotypic and morphologic features and carry favorable prognosis in MDS. These mutations are often found in patients carrying less deleterious abnormalities [e.g., del(5q)] and their founder clonal nature has been uncovered through experimental studies. Recent studies unveiled the occurrence of SF3B1 mutations in de novo AML and low complete remission rate when combined with other mutations (e.g., DNMT3A). To investigate whether SF3B1 mutations were unequivocally frequent in inv(3)/t(3;3) AML compared to other splicing factor mutations, we moved forward in dissecting the clinical, morphologic and molecular profiles of these cases. We analyzed results from whole exome sequencing and targeted deep sequencing from the Cleveland Clinic and publicly available data of AML with inv(3)/t(3;3) (de novo AML, n=32; secondary AML from antecedent myeloid neoplasms, n=11; t-AML, n=1). In our cohort, mutations in the most common components of the RNA splicing machinery (SF3B1, SRSF2, U2AF1, ZRSR2) were observed in 27% (n=12) of the patients. Among splicing factor mutations, SF3B1 was the most mutated gene (77%; 10/13 total mutations); 7 cases had inv(3) and 3 had t(3;3). Mutations were observed at canonical sites: K700E (70%) and K666N (30%) with no difference compared to the hotspots observed in MDS. Sixty% of patients were female. Median age was 61 years (range, 36-73). Anemia was present in 50%, leukopenia in 10% and thrombocytopenia in 50% of the patients. For 40% of the cases, BM smears for iron staining was available and showed absence of ringed sideroblasts. Complex karyotype (CK) was present in 20% of the patients; -7/del(7q) was present as the only cytogenetic abnormality in 30% or with CK in 10% pf the cases. Variant allele frequency (VAF) of SF3B1mutations in inv(3)/t(3;3) was not different than the those without inv(3)/t(3;3) (42% vs 40%). Survival analysis was performed in 3 subgroups: SF3B1MT AML (n=70), SF3B1MT AML + inv(3)/t(3;3) (n=10), AML + inv(3)/t(3;3) (n=34). SF3B1MT AML + inv(3)/t(3;3) and AML + inv(3)/t(3;3) had similar OS (11.7 vs 9.7 months) which was shorter than the that of SF3B1MT AML without any inv(3)/t(3;3) (19.4 months, P=0.002) suggesting that SF3B1MT in the context of inv(3)/t(3;3) might hold a different prognostic significance strongly due to the presence of inv(3)/t(3;3). Given this observation, we delved into the clonal diversity of SF3B1 mutations and its co-occurrence with other molecular mutations. Comparison of VAFs showed that SF3B1 mutations in relation to other mutations were dominant/founder in 30%, secondary/subclonal in 20% while co-dominant to another gene (VAF differences <5%) in 50% of the cases. The most common co-dominant gene mutation was GATA2 (60%, 3/5). Top mutations by frequency were in GATA2 (30%), ASXL1 (20%) and NRAS (20%). Hemizygous GATA2 mutations were detected in 15% of SF3B1MT AML + inv(3)/t(3;3). In our cohort, other RAS gene mutations were detected in 10% of the patients each, including CBL, NF1 and PTPN11). One SF3B1MT AML + inv(3)/t(3;3) case also harbored a SRSF2 mutation with a parallel median VAF of 40% and 41%, respectively. The results of our study are summarized in Fig. 1. In sum, we describe that SF3B1 mutations occur in combination with inv(3)/t(3;3) in AML and might represent a subclass of this entity in which lesions in SF3B1 gene could potentially hide a cryptic association between splicing abnormalities and disease phenotypes. Figure 1 Disclosures Maciejewski: Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria.

Expression of c-mpl mRNA, the receptor for thrombopoietin, in acute myeloid leukemia blasts identifies a group of patients with poor response to intensive chemotherapy.

1997 ◽  
Vol 15 (6) ◽  
pp. 2262-2268 ◽  
Author(s):  
M Wetzler ◽  
M R Baer ◽  
S H Bernstein ◽  
L Blumenson ◽  
C Stewart ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Prognostic Factor ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Prognostic Significance ◽  
Poor Response ◽  
Significant Difference ◽  
De Novo Aml ◽  
Cd34 Expression ◽  
Acute Myeloid

PURPOSE c-mpl, the human homolog of v-mpl, is the receptor for thrombopoietin. Given that c-mpl expression carries an adverse prognosis in myelodysplastic syndrome and given the prognostic significance of expression of other growth factor receptors in other diseases, we attempted to determine whether c-mp/mRNA expression is a prognostic factor in acute myeloid leukemia (AML). PATIENTS AND METHODS We analyzed bone marrow samples from 45 newly diagnosed AML patients by reverse-transcription polymerase chain reaction. RESULTS Samples from 27 patients (60%) expressed c-mpl mRNA (c-mpl+); their clinical and laboratory features were compared with those of the 18 patients without detectable levels of c-mpl(c-mpl-). No significant differences in age, sex, leukocyte count, French-American-British subtype, or karyotype group were found. c-mpl+ patients more commonly had secondary AML (41% v 11%; P = .046) and more commonly expressed CD34 (67% v 12%; P = .0004). There was no significant difference in complete remission (CR) rate. However, c-mpl+ patients had shorter CR durations (P = .008; median, 6.0 v > 17.0 months). This was true when only de novo AML patients were considered and when controlling for age, cytogenetics, or CD34 expression. There was a trend toward shorter survival in c-mpl+ patients (P = .058; median, 7.8 v 9.0 months). CONCLUSION These data suggest that c-mpl expression is an adverse prognostic factor for treatment outcome in adult AML that must be considered in the analysis of clinical studies using thrombopoietin in AML.

Genome-Wide Genotyping of Acute Myeloid Leukemia with t(9;11) Reveals New Recurrent Genomic Alterations,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3546-3546
Author(s):  
Michael W.M. Kühn ◽  
Lars Bullinger ◽  
Jennifer Edelmann ◽  
Jan Krönke ◽  
Gröschel Stefan ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Genetic Alterations ◽  
Mixed Lineage Leukemia ◽  
Genetic Event ◽  
Genome Wide ◽  
De Novo Aml ◽  
Paired Analysis ◽  
Acute Myeloid

Abstract Abstract 3546 Rearrangements of the mixed lineage leukemia (MLL) gene are associated with the development of acute leukemia, and a variety of translocation partners have been described to date. In acute myeloid leukemia (AML), the translocation t(9;11)(p22;q23), resulting in the MLLT3-MLL fusion gene, is the most common genetic event involving MLL. The translocation t(9;11) can occur de novo, or as a consequence of previous chemotherapy (t-AML). Both types exhibit significant biological and clinical heterogeneity, and cooperating genetic events have been implicated underlying these heterogeneous phenotypes. To identify additional genomic abnormalities in AML with t(9;11), we performed high-resolution, genome-wide analysis of DNA copy number alterations (CNA) and copy neutral loss of heterozygosity (CN-LOH) using Affymetrix 6.0 single nucleotide polymorphism (SNP) microarrays in 34 AMLs with t(9;11) [de novo AML, n=22; t-AML, n=12]. Samples were also analyzed for AML-associated mutations: FLT3 [internal tandem duplication (ITD; 2/33); tyrosine kinase domain (TKD; 2/26)], NPM1 (0/28), CEBPA (0/23), IDH1 (0/28), IDH 2 (0/28), DNMT3A (0/19), NRAS (0/6); and deregulated expression of EVI1 (8/16). Control DNA from remission bone marrow or peripheral blood was available for paired analysis in 12 (33%) cases. Data were processed using reference alignment, dChipSNP, and circular binary segmentation. Paired analysis revealed a mean of 1.9 somatic CNAs per case (range: 0–12); 45% of cases lacked any CNAs. Deletions were more common than gains (1.73 losses/case vs. 0.25 gains/case; p =0.04). There were no significant differences in the mean number of CNAs between de novo and therapy-related cases (de novo AML: 1.0, range: 0–2; t-AML: 2.7, range: 0–12; p =0.93). Recurrent deletions were detected at chromosomal bands 7q36.1–36.2 (n=2) and at the chromosomal translocation breakpoint at 11q23 (n=2). The del(7q36.1–36.2) overlapped with a minimally deleted region at 7q36.1 that we previously identified in 8% of core-binding factor AML containing only 4 genes (PRKAG2, GALNT11, GALNTL5 and MLL3). The only gene contained in both regions was MLL3, a member of the mixed-lineage leukemia gene family. The most recurrent CNA was trisomy 8 (n=5), also detected by conventional cytogenetics in all 5 cases. Novel recurrent focal gains were identified at 9p22.1 (n=2; size: 341 Kb) and at 13q21.33-q22.1 (n=2; size: 1021 Kb) with each region containing genes potentially involved in cancer pathogenesis (ACER2 in 9p; KLF5 in 13q). Analysis of CN-LOH revealed no such lesion in any of the cases. In summary, our data provide a comprehensive survey of CNAs in a well characterized cohort of AMLs with t(9;11). These data demonstrate a very low occurrence of CNAs, with no significant differences between de novo and therapy-related cases and complete absence of CN-LOH. Interestingly, a number of novel recurrent secondary genetic alterations were identified. Determining the functional role of these lesions in leukemogenesis and drug resistance should provide new insights into t(9;11)-bearing AMLs. Disclosures: No relevant conflicts of interest to declare.

Prognostic Significance of β-2 Microglobulin Levels in Acute Myeloid Leukemia: Analysis of 1293 Patients.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 802-802
Author(s):  
Apostolia-Maria Tsimberidou ◽  
Hagop M. Kantarjian ◽  
Michael J. Keating ◽  
Susan O’Brien ◽  
Sijin Wen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Uric Acid ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Prognostic Significance ◽  
Elevated Serum ◽  
Cell Counts ◽  
Younger Age ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Introduction: β-2 Microglobulin (β2M) is a single polypeptide chain that is linked non-covalently to the major histocompatibility complex class I cell surface antigen. Its specific function is unknown, but serum β2M levels reflect membrane turnover (tumor mass and growth rate) and renal function. Elevated serum β2M levels are associated with poor survival in several hematologic malignancies, but its prognostic significance in acute myeloid leukemia (AML) is unknown. The purpose of this study was to determine the association between β2M levels and pretreatment characteristics and clinical outcomes in newly diagnosed AML. Patients and Methods: From 1990 to 2005, β2M levels were prospectively measured in 1293 patients with AML. Serum β2M was quantified by radioimmunoassay (normal range, 0.7–2.0 mg/L). Results: The median patient age was 61 yrs (range, 16–89 yrs); 54% were >60 yrs. Cytogenetics were favorable in 7% of patients, intermediate in 60%, poor-risk in 29%, and 4% of patients had insufficient metaphases. Zubrod performance status (PS) was 0–1 in 73% of patients, 2 in 20%, and 3–4 in 7%. Eighty-five percent had de novo AML, and 91% received Ara-C-based therapy. High β2M levels were more common in patients who were older (cor=0.22); had high early risk of mortality (ERM) score (cor =0.33); high levels of creatinine (cor=0.63), and uric acid (cor=0.29), high white blood cell counts (cor=0.26), or circulating monocytes (cor = 0.23); prolonged prothrombin time (PT) (cor=0.26); worse PS (cor=0.27); and low albumin levels (cor=−0.22)(p<0.001 for all variables). High β2M levels were correlated with worse-risk cytogenetics (p=0.03), RAS mutation (p=0.003), baseline infection (p=0.04), and secondary AML (p=0.01). The median follow-up of surviving patients was 3.8 yrs. In multivariate analysis, independent factors predicting response were younger age (p<0.0001), better-risk cytogenetics (p<0.0001), Ara-C-based therapy (p<0.0001), lower levels of β2M (p=0.0001), shorter PT (p=0.006), de novo AML (p=0.007), lower LDH levels (p=0.02), and lower bilirubin levels (p=0.03). Factors independently prognostic of longer survival were younger age (p<0.0001), better-risk cytogenetics (p<0.0001), better PS (p<0.0001), de novo AML (p<0.0001), lower serum uric acid levels (p=0.0001), lower LDH levels (p=0.0007), shorter PT (p=0.0009), lower β2M levels (p=0.003), higher hemoglobin levels (p=0.005), Ara-C-based therapy (p=0.007), and lower bilirubin levels (p=0.02). Factors independently prognostic of longer event-free survival (EFS) were younger age (p<0.0001), better-risk cytogenetics (p<0.0001), Ara-C-based therapy (p<0.0001), de novo AML (p=0.0001), better PS (p=0.0003), lower uric acid levels (p=0.0004), lower LDH levels (p=0.001), lower β2M levels (p=0.002), higher hemoglobin levels (p=0.003), shorter PT (p=0.02), and lower bilirubin levels (p=0.045). Conclusions: Elevated serum β2M levels are an independent adverse prognostic factor for response, survival, and EFS in the context of established prognostic factors for AML. Outcomes by β2M levels β2M (mg/L) <2.0 2.0–2.9 3.0–3.9 ≥4.0 p-value No. pts. 251 448 260 334 CR, % 67 66 54 39 <0.0001 Median EFS (yrs) 0.69 0.58 0.31 0.15 <0.0001 Median Survival (yrs) 1.33 1.19 0.63 0.42 <0.0001

FLT3, NPM1 and MLL Mutations Help Risk Stratification in Pediatric Acute Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1574-1574
Author(s):  
Shuhong Shen ◽  
Yin Liu ◽  
JingYan Tang ◽  
Long-Jun Gu
Keyword(s):  
Acute Myeloid Leukemia ◽  
Risk Stratification ◽  
Myeloid Leukemia ◽  
Tandem Duplication ◽  
De Novo ◽  
Genetic Alterations ◽  
Npm1 Mutation ◽  
De Novo Aml ◽  
Pediatric Aml ◽  
Acute Myeloid

Abstract Abstract 1574 Poster Board I-600 Introduction Acute myeloid leukemia (AML) is a heterogeneous disease which harbors various genetic alterations. Among theses genetic events, Mutations of FLT3, NPM1, MLL and other genes often predict prognosis, particularly in cases cytogenetic normal (CN-AML). Could these be criteria for risk stratification in Pediatric AML ? Patients and Methods 155 cases of de novo AML were diagnosed routinely according to morphology, immunology, cytogenetics, and molecular biology examination on bone marrow (BM) aspirates between Jan. 2002 and Dec. 2008. All patients received chemotherapy according to the AML-XH-99 protocol, which consist of Daunorubicin, Cytosine arabinoside, Etoposide, Homoharringtonine. For acute promyelocytic leukemia, all-trans retinoic acid and Arsenic trioxide were also included. Meanwhile, total RNA of leukemic cells form all diagnostic BM samples were extracted, and then reverse transcribed. MLL partial tandem duplication (MLL/PTD) fusion transcripts were screened by real-time quantitative polymerase chain reaction. FLT3 internal tandem duplication (FLT3/ITD), FLT3 tyrosine kinase domain mutation (FLT3/TKD) and NPM1 mutation were examined by High resolution melting analysis. Results Of the 155 children with de novo AML, 121(78.1%) had received chemotherapy for more than one week with data available for analysis. Among them, 55(45.5%) was cytogenetically normal (CN-AML). In this total cohort of patients 49(27.09%) had FLT3/ITD (32.70% in CN-AML), 14 (9.03%) had FLT3/TKD (7.30% in CN-AML), 62 (40%) had NPM1 mutation (49% in CN-AML), and additional 8 (5.16%) had MLL/PTD (5.50% in CN-AML). In this cohort of patients 98 (63.22%) had at least one mutation. The clinical outcomes were listed in table 1. Generally, patients with FLT3 mutation (ITD or TKD mutation) usually have worse results after chemotherapy, as reported previously by other researchers. Meanwhile, NPM1 mutations usually predict better prognosis in our cohort of AML patients. MLL/PTD always predicts the worst outcome in AML as other MLL rearrangements in leukemia. Among CN-AML patients, 5-year EFS and OS were similar to whole cohort of patients according to those mutations. Cox regression analysis in a univariate model revealed that the presence of FLT3/ITD and NPM1 was significant prognostic factor of EFS, (P<0.05). We therefore proposed a molecular-risk classification of pediatric AML patients based on the data we got in this study. For the newly classified groups of low, medium and high risk groups, EFS rate was 62.03%±8.42%, 45.42%±4.52%, and 14.85%±2.99%, respectively, P=0.00. CRD for the 3 groups was 27.69±21.34 months, 22.62±19.64 months, 13.26±11.95 months, respectively, p=.022. Our results indicate that combinations of these couple of molecular events may be the useful tool for further classify AML in children. Disclosures No relevant conflicts of interest to declare.

Impact of Molecular Clonality on Survival in Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1385-1385
Author(s):  
Wade L Schulz ◽  
Thomas JS Durant ◽  
Henry Rinder ◽  
Christopher A Tormey ◽  
Richard Torres ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Tumor Heterogeneity ◽  
De Novo ◽  
Prognostic Significance ◽  
Recurrent Mutations ◽  
Early Survival ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Background: Tumor heterogeneity has been documented in several malignancies and is generally associated with more aggressive disease and poorer prognosis. While heterogeneity has been documented in acute myeloid leukemia (AML), risk prognosis in AML is currently assessed by cytogenetics and the presence of recurrent mutations in genes such as FLT3 and NPM1, which are typically tested on a single gene basis. Prior approaches to identify molecular clonality have been laborious and therefore of limited clinical utility. The advent of next generation sequencing (NGS), however, allows for the rapid assessment of subclones within tumor populations. Currently, the prognostic significance of tumor heterogeneity in AML is not well defined. Therefore, this pilot study assessed the clinical significance of molecular clonality in AML using data generated by an NGS platform. Methods: We selected patients with de novo AML who had blood or bone marrow submitted for sequencing at initial diagnosis. Patients who subsequently elected for comfort measures only without receiving AML-directed therapy were excluded. Study patients were sequenced with a 25 gene NGS panel on the Ion Torrent platform. This panel included genes that have been shown to be frequently mutated in AML and which lead to increased cellular proliferation or impaired differentiation, with particular emphasis on therapeutic and prognostic mutations. Germline mutations, identified by allelic fraction and/or minor allele frequency, were excluded. Remaining somatic mutations were analyzed with software employing a variational Bayesian algorithm to predict tumor heterogeneity such that patients were assessed for the presence of tumor heterogeneity (≥2 predicted clones) at the time of diagnosis. Heterogeneity was recorded and compared to several clinical parameters, including post-chemotherapy survival at 120 days, patient age, gender, karyotype, and association with the recurrent genetic mutations NPM1, FLT3-ITD, and CEBPA. Results: Twenty patients met the study criteria of de novo AML and elected to receive therapy. The mean age at diagnosis was 59 years (38-77 years); overall survival was 75% at 120 days. Half of the patients (n=10) were determined to have ≥2 clones. Patients with either a complex karyotype or the FLT3-ITD mutation were classified as high risk (n=11). While survival at 120 days was lower in the high risk group (64%) compared to normal risk subjects (89%), this difference did not reach statistical significance (p=0.19). By contrast, patients with tumor heterogeneity (≥2 clones) had significantly lower 120 day survival (50%) when compared to AML patients with a single clone (100%) (p=0.01). There was no correlation between patients with multiple clones and high risk classification (p=0.18). Conclusions: These pilot data present some of the first prospective evidence that heterogeneity detected by NGS is an adverse prognostic indicator for early survival in de novo AML post-chemotherapy. This finding may not be surprising given that the presence of tumor heterogeneity has been shown to confer adverse prognostic risk in several solid malignancies. Still, this early impact of molecular clonality in AML may have important consequences on choice of therapy. Further prospective studies are needed to confirm our findings and to determine the long-term outcomes in AML patient subsets, as well as examining whether a distinct approach to therapy in AML patients with clonal heterogeneity leads to improved early survival. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.

scholarly journals Clonal Hematopoiesis Landscape in Patients with De Novo Acute Myeloid Leukemia By Deep Sequencing

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 598-598
Author(s):  
Mariam Ibáñez ◽  
Alexander Neef ◽  
Carmen Martínez-Losada ◽  
Esperanza Such ◽  
Desiree Company ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Deep Sequencing ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Clonal Evolution ◽  
Genetic Alterations ◽  
Prognostic Impact ◽  
Clonal Hematopoiesis ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Purpose: Acute myeloid leukemia (AML) is associated with progressive accumulation of genetic alterations in hematopoietic progenitors. Massive sequencing allows inference of the clonal architecture of hematologic malignancies, by determining the presence of subclones, their genetic composition and evolution. The objective of the present study was to determine the spectrum of mutations present at relapse and define the proportion of cellular clones and the genetic architecture of the evolution of patients with de novo AML. Methods: Paired samples (diagnostic/relapse) of 44 patients of the University Hospital La Fe with de novo AML and treated with consecutive PETHEMA schemes were studied. The samples were provided by the Biobanco La Fe. The median age was 59 years (range 17 - 89); 21M/13F; 17 patients with normal karyotype; 14 patients with FLT3-ITD positive and 9 with mutations in NPM1. Using an amplicon panel (Ampliseq, Life Technologies) for deep sequencing (10.000x) with an Ion Torrent Proton, the complete coding regions of the following genes were sequenced, BCOR, BRAF, CDKN2A, CEBPA, DNMT3A, ETV6, EZH2, GNAS, LUC7L2, NF1, PHF6, PTPN11, RAD21, RPS14, SF1, SF3A1, SMC3, SPARC, SRSF2, STAG2 and ZRSR2, as well as, the hotspot regions of ASXL1, MPL, NPM1, JAK2, KRAS, NRAS, TET2, U2AF1, KIT, IDH1, RUNX1, IDH2, SETBP1, TP53, WT1, CBL, SF3B1 and FLT3. Primary bioinformatic analysis was performed using an in-house protocol and variants were selected based on VAF ≥ 1%, its absence in the healthy population (UCSC Common SNPs; MAF < 0.01) and its putative effect on the protein. Results: At least one alteration was detected in 98% of patients, (n = 43). At a mean sequencing depth of 8967x, in total, 249 mutations were detected with an average of 3.3 mutations per patient and sample (range 0 - 8). Comparing the two time points, we noted that 45% of the mutations were present at both moments, with rather similar VAF values. However, 24% were acquired during progression while 31% went missing at the time of relapse. Regarding the mutated genes analyzed at diagnosis, in 8 of 44 patients one single gene clone was detected, in 26 two subclones and in 10 three or more subclones. In addition, two different patterns of clonal evolution were detected. In model 1 the dominant founder clone persisted at relapse (n = 32, 71%), occasionally acquiring new changes, either in the same clone (n = 5) or in a new subclone (n = 17). In model 2 the founder clone was displaced at relapse by new subclones (n = 12, 29%), probably due to selective pressure through competition between subclones or as a consequence of the chemotherapy. Furthermore, the clonal hematopoiesis models did not show an association with clinical variables or prognostic impact on OS or EFS (P = 0.317; P = 0.12, respectively). Conclusions: AML cells can acquire additional mutations at relapse. Some of those may contribute to the clonal selection responsible for disease progression. Two models of clonal evolution were observed: model 1, where the dominant founder clone persists during relapse, and, model 2, where the founder clone is displaced by new cell subclones, displaying, both models, a similar impact on outcome. Financed by the Spanish Foundation of Hematology (FEHH), PI12/01047, RD12/0036/0014, PIE13/00046, PI13/01640, PI13/02837, PT13/0010/0026, PI14/01649, ACOMP2015/0335 and PROMETEOII/2015/study/025. Disclosures No relevant conflicts of interest to declare.

scholarly journals Mutation of NPM1 and FLT3 Genes in Acute Myeloid Leukemia and Their Association with Clinical and Immunophenotypic Features

2013 ◽  
Vol 35 ◽  
pp. 581-588 ◽  
Author(s):  
Pradeep Singh Chauhan ◽  
Rakhshan Ihsan ◽  
L. C. Singh ◽  
Dipendra Kumar Gupta ◽  
Vishakha Mittal ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Fusion Gene ◽  
Genetic Alterations ◽  
Prognostic Indicators ◽  
White Blood Count ◽  
Npm1 Mutation ◽  
De Novo Aml ◽  
Acute Myeloid

Background.Mutations in NPM1 and FLT3 genes represent the most frequent genetic alterations and important diagnostic and prognostic indicators in patients with acute myeloid leukemia (AML).Objective.We investigated the prevalence and clinical characteristics of NPM1 and FLT3 mutations in 161 patients of de novo AML including adults and children.Results.NPM1 mutation was found in 21% and FLT3 mutation in 25% of the AML patients. Thirteen (8%) samples were positive for both NPM1 and FLT3/ITD mutations. Adult patients had significantly higher frequency of NPM1 mutation than children (25.8% versus 8.8%;P=0.02). Further, NPM1 mutation was found to be more frequent in patients above 45 years of age (P=0.02). NPM1 mutation was significantly associated with higher platelet count (P=0.05) and absence of hepatosplenomegaly (P=0.01), while FLT3/ITD mutation was associated with higher white blood count (P=0.01). Immunophenotypically, NPM1 mutation was associated with the lack of CD34 (P<0.001) and HLD-DR expression (P<0.001), while FLT3/ITD mutation was positively associated with the expression of CD7 (P=0.04). No correlation was found between NPM1 mutation and fusion gene. Interestingly, FLT3/ITD mutation was found to be inversely associated with AML/ETO fusion gene (P=0.04).Conclusions.The results suggest that distinct clinical and immunophenotypic characteristics of NPM1 and FLT3/ITD mutations present further insight into the molecular mechanism of leukemogenesis.

scholarly journals Distinct clinical and biological characteristics of acute myeloid leukemia with higher expression of long noncoding RNA KIAA0125

2020 ◽  
Author(s):  
Yu-Hung Wang ◽  
Chien-Chin Lin ◽  
Chia-Lang Hsu ◽  
Sheng-Yu Hung ◽  
Chi-Yuan Yao ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Noncoding Rna ◽  
De Novo ◽  
Remission Rate ◽  
Prognostic Significance ◽  
Multivariable Analysis ◽  
Disease Free Survival ◽  
Biological Characteristics ◽  
Acute Myeloid

AbstractExpression of long non-coding RNA KIAA0125 has been incorporated in various gene expression signatures for prognostic prediction in acute myeloid leukemia (AML) patients, yet its functions and clinical significance remain unclear. This study aimed to investigate the clinical and biological characteristics of AML bearing different levels of KIAA0125. We profiled KIAA0125 expression levels in bone marrow cells from 347 de novo AML patients and found higher KIAA0125 expression was closely associated with RUNX1 mutation, but inversely correlated with t(8;21) and t(15;17) karyotypes. Among the 227 patients who received standard chemotherapy, those with higher KIAA0125 expression had a lower complete remission rate, shorter overall survival (OS) and disease-free survival (DFS) than those with lower expression. The prognostic significance was validated in both TCGA and GSE12417 cohorts. Subgroup analyses showed that higher KIAA0125 expression also predicted shorter DFS and OS in patients with normal karyotype or non-M3 AML. In multivariable analysis, higher KIAA0125 expression remained an adverse risk factor independent of age, WBC counts, karyotypes, and mutation patterns. Bioinformatics analyses revealed that higher KIAA0125 expression was associated with hematopoietic and leukemic stem cell signatures and ATP-binding cassette transporters, two predisposing factors for chemoresistance.

Antileukemic activity of rapamycin in acute myeloid leukemia

Blood ◽  
2005 ◽  
Vol 105 (6) ◽  
pp. 2527-2534 ◽  
Author(s):  
Christian Récher ◽  
Odile Beyne-Rauzy ◽  
Cécile Demur ◽  
Gaëtan Chicanne ◽  
Cédric Dos Santos ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Mammalian Target Of Rapamycin ◽  
Cell Types ◽  
Mtor Inhibition ◽  
Growth And Survival ◽  
Clinical Responses ◽  
De Novo Aml ◽  
Acute Myeloid

AbstractThe mammalian target of rapamycin (mTOR) is a key regulator of growth and survival in many cell types. Its constitutive activation has been involved in the pathogenesis of various cancers. In this study, we show that mTOR inhibition by rapamycin strongly inhibits the growth of the most immature acute myeloid leukemia (AML) cell lines through blockade in G0/G1 phase of the cell cycle. Accordingly, 2 downstream effectors of mTOR, 4E-BP1 and p70S6K, are phosphorylated in a rapamycin-sensitive manner in a series of 23 AML cases. Interestingly, the mTOR inhibitor markedly impairs the clonogenic properties of fresh AML cells while sparing normal hematopoietic progenitors. Moreover, rapamycin induces significant clinical responses in 4 of 9 patients with either refractory/relapsed de novo AML or secondary AML. Overall, our data strongly suggest that mTOR is aberrantly regulated in most AML cells and that rapamycin and analogs, by targeting the clonogenic compartment of the leukemic clone, may be used as new compounds in AML therapy.

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