Q141K Polymorphism of ABCG2 Protein Is Associated with Poor Prognosis In Adult Acute Myeloid Leukemia Treated with a Idarubicin-Based Chemotherapy Protocol

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4941-4941
Author(s):  
Daniela Damiani ◽  
Mario Tiribelli ◽  
Angela Michelutti ◽  
Dora Fabbro ◽  
Alessandra Franzoni ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Anticancer Drugs ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Divergent Evolution ◽  
Cell Physiology ◽  
Abc Proteins ◽  
Abcg2 Protein ◽  
The Impact ◽  
Acute Myeloid

Abstract Abstract 4941 Since the multidrug resistance phenotype was first observed 30 years ago, other 48 proteins, belonging to an evolutionary highly conserved family of transport proteins, named ABC proteins, has been identified and grouped in eight subclasses, according to divergent evolution. In eukaryotes, ABC proteins are involved in transport across the membrane to extracellular space or into intracellular organelles playing an important role in cell physiology. Almost three distinct subfamilies (B, C and G) have been recognized to transport a wide variety of amphipatic or hydrophobic molecules, including most of anticancer drugs compounds, affecting drug absorption, disposition, metabolism, excretion and toxicity (ADMEtox) and has been associated to chemotherapy failure in solid and hematologic neoplasia. In particular the role of ABCG2 has been pinpointed over the past years for its high expression on primitive hematopoietic and on progenitors cells and for its ability to confer to the cancer cell the properties of cancer stem cell, with increased survival capacity. At present over 40 single nucleotide polymorphisms of ABCG2 protein have been identified. Among them the 421C>A (Q141K) variant has been shown able to alter protein function and to modify in vitro sensitivity to many anticancer drugs, compared to the wild type protein. In the present paper we have evaluated the incidence and the impact on therapy outcome in a series of 100 caucasic patients with acute myeloid leukemia, receiving the same chemotherapy program including idarubicin. Q141K polymorphism was detected in 19/100 (19%) patients, without correlation with any clinical-biological characteristic at diagnosis (such as sex, age, peripheral blast count, FAB subtype, karyotytpe, CD34 expression). ABCG2 protein was overexpressed in 10/19 (52.6%) of mutated patients and in 37/83 (44.5%) of patients expressing the wt form of ABCG2 and no difference in intensity of ABCG2 expression was observed in the two groups. Again no difference in ABCG2 mRNA transcription was detected between patients carrying wt or polymorphic protein. Complete remission rate was comparable in wt and mutated patients (38/81, 45,7% vs 10/19, 52,6%). However patients with Q141K polymorphism (irrespective to the intensity of expression of ABCG2) protein) had a leukemia free survival comparable to patients overxpressing wt protein, and significantly shorter than patients without wt ABCG2 overepxression (chi square 12,2, p=0,002, logrank test). In conclusion our data demonstrated Q141K polymorphism of ABCG2 transporter protein identified a subset of patients with high probability of relapse when treated with idarubicin suggesting that other drugs should be considered in consolidation/maintenance treatment to improve patients outcome. Finally the impact of Q141K polymorphism on treatment toxicity is under investigation. Work supported by PRIN 2007WEYB34-004 Disclosures: No relevant conflicts of interest to declare.

Inhibition of HDAC8 Reactivates p53 and Abrogates Leukemia Stem Cell Activity in CBFβ-SMMHC Associated Acute Myeloid Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 363-363
Author(s):  
Jing Qi ◽  
Qi Cai ◽  
Sandeep Singh ◽  
Ling Li ◽  
Hongjun Liu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Bone Marrow Cells ◽  
Conflicts Of Interest ◽  
Cell Activity ◽  
Disease Free Survival ◽  
Hematopoietic Stem ◽  
The Impact ◽  
Acute Myeloid

Abstract The inv(16)-created CBFβ-SMMHC fusion protein inhibits differentiation of hematopoietic stem and progenitor cells (HSPCs) and creates pre-leukemic populations predisposed to acute myeloid leukemia (AML) transformation. However, the molecular mechanism underlying the leukemogenic function of CBFβ-SMMHC has been elusive. Given the low TP53 mutation rate in AML, alternative mechanisms disrupting p53 function are expected. We showed thatCBFβ-SMMHC impairs p53 acetylation and p53 target gene activation through formation of an aberrant protein complex with p53 and HDAC8 (Blood, 120: A772; 122(21): 224). We now show that CBFβ-SMMHC binds to p53 and HDAC8 independently through distinct regions and that HDAC8 mediates the deacetylation of p53 associated with CBFβ-SMMHC. In addition, we generated mice carrying a floxed Hdac8 (Hdac8f) allele and crossed with Cbfb56M/+/Mx1-Cre (Kuo YH et al, Cancer Cell 2006). Deletion of Hdac8 signifiacntly (p<0.0001) reduced the incidence of AML and prolonged disease-free survival. Pharmacologic inhibition of HDAC8 activity with HDAC8-selective inhibitors (HDAC8i) reactivates p53 and selectively induces apoptosis of inv(16)+ AML CD34+ cells while sparing normal HSPCs. To test the effect of HDAC8i on LSC engraftment and leukemia-initiating capacity, we generated Cbfb56M/+/Mx1-Cre mice with a Cre-reporter line expressing tdTomato fluorescence protein following Cre-mediated recombination. AML cells (dTomato+/cKit+) treated with HDAC8i (22d) ex vivo showed reduced engraftment (p=0.025) and enhanced survival (p=0.025) in transplanted mice. To examine whether HDAC8i 22d treatment affects the engraftment capacity on surviving cells, we transplanted equal number (2 x 106) of AML cells treated with either 22d or vehicle in another cohort of mice (n=4). We show that HDAC8i 22d treatment reduced the engraftment of dTomato+/cKit+ AML cells and enhanced survival, suggesting that the engraftment capacity is altered in addition to reducing AML cell survival. We next performed preclinical studies to determine the efficacy of in vivo administration of HDAC8i 22d. AML transplanted mice were randomized into two groups, one group treated with vehicle and the other treated with HDAC8i 22d for 2 weeks. Flow cytometry analysis revealed significantly reduced frequency (p=0.0097) and number (p=0.0101) of dTomato+/cKit+ AML cells in the bone marrow and spleen of 22d treated mice compared to vehicle treated group. To further assess the impact on LSC activity, we transplanted bone marrow cells from these treated mice into secondary recipients and analyzed for AML engraftment. Significant reduction in the frequency (p<0.0001) and the number (p=0.0006) of dTomato+/cKit+ AML cells was observed in the bone marrow and spleen. Furthermore, HDAC8i 22d treated transplants showed no signs of leukemia while vehicle treated transplants are moribund with aggressive AML. These results indicate that HDAC8 inhibition by 22d treatment effectively eliminates engraftment and leukemia-initiating capacity of AML LSCs. In conclusion, our studies identify a novel post-translational p53-inactivating mechanism and demonstrate selective HDAC8 inhibition as a promising approach to target inv(16)+ AML LSCs. Disclosures No relevant conflicts of interest to declare.

Prognostic Implication of Chromosome 17 Abnormalities in the Context of Monosomal Karyotype (MK) in Patients with Acute Myeloid Leukemia (AML) and Complex Cytogenetics

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1495-1495
Author(s):  
Aziz Nazha ◽  
Vijaya R Bhatt ◽  
Graciela Nogueras-Gonzalez ◽  
Tapan Kadia ◽  
Jorge E. Cortes ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Chromosome 17 ◽  
Cancer Center ◽  
Poor Performance Status ◽  
Complex Karyotype ◽  
The Impact ◽  
Monosomal Karyotype ◽  
Acute Myeloid

Abstract Abstract 1495 Background: Monosomal karyotype (MK) is a stronger indicator of dismal clinical outcome than complex karyotype alone among patients with acute myeloid leukemia (AML) (J Clin Oncol 26: 4791–4797). We previously reported that Chromosome 17 abnormalities are associated with worse overall and relapse free survival among patients with AML and complex karyotype (ASH 2009, Borthakur et al #1501). Objectives: To investigate the impact of chromosome 17 abnormalities on the overall survival (OS) and eventfree survival (EFS) in AML patients (pts) with complex cytogenetics after monosomal karyotype is taken into account. Patients and Method: We conducted a review of 1086 pts with newly diagnosed AML treated at MD Anderson Cancer Center between January 1998 and December 2007. Four hundred eighty-three pts had complex cytogenetics defined by the presence ≥ 3 unrelated cytogenetic abnormalities and 37 patients were excluded from the final analysis because of poor performance status (≥ 3 ECOG) at presentation, a population least likely to be offered therapy. Monosomal karyotype (MK+) was defined as presence of at least an autosomal monosomy and a structural chromosomal abnormality or at least two autosomal monosomies. Cox proportional hazards regression was used to model the association between potential prognostic factors and survival (OS and EFS). The Kaplan-Meier product limit method was used to estimate the median time to death or event. Statistical analysis was performed using STATA/SE version 11.2 statistical software (Stata Corp. LP, College Station, TX). Result: Of the 446 pts with complex cytogenetics, 342 (76.7%) pts had MK and 183 (41.0%) pts had chromosome 17 abnormalities (Ch17+). The median age for the entire cohort was 64 years (range: 13–86). One hundred eighty-one (40.6%) pts achieved complete remission (CR/CRp) after induction chemotherapy, 173 (38.8%) pts had resistant disease and 89 (19.9%) had early death. Median OS among pts with MK+ was 4.7 months compared with 8.4 months in MK- patients (Hazard ratio [HR]: 1.37, 95%CI: 1.09–1.72, p=0.006) and was 4.4 months among pts with Ch17+ compared with 6.7 months for Ch17- (HR: 1.28, 95%CI: 1.05–1.55, p=0.014) (Fig.1). Within the group of patients with MK+, additional presence of Ch17 abnormalities was associated with worse OS (HR: 1.23, 95%CI: 1.00, 1.53, p=0.046).On multivariate analysis age, high WBC and MK+ (HR: 1.47, 95%CI: 1.17–1.85, p=0.001) were the variables associated with shorter OS to the exclusion of Ch17+. On the other hand age, higher WBC and Ch17+ (HR: 1.25, 95%CI: 1.04–1.50, p=0.019) were the variables that correlated to shorter EFS to the exclusion of MK+. Conclusion: Among patients with AML and complex cytogenetics, monosomal karyotype is associated with poor outcomes. Additional presence of chromosome 17 abnormalities further worsen outcome in this particularly poor-risk patients with AML. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Outcome Among Adolescents and Young Adults with Acute Myeloid Leukemia at Pediatric Versus Adult Centers: A Population-Based Study Using the IMPACT Cohort

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4749-4749
Author(s):  
Sumit Gupta ◽  
Nancy Baxter ◽  
Jason Pole ◽  
Cindy Lau ◽  
Rinku Sutradhar ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Young Adults ◽  
Acute Lymphoblastic Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Population Based ◽  
Adolescents And Young Adults ◽  
The Impact ◽  
Acute Myeloid

Background: Survival outcomes among adolescents and young adults (AYA) with acute myeloid leukemia (AML) remain poor. In AYA with acute lymphoblastic leukemia, outcomes differ between patients treated in pediatric vs. adult centers. This has not been well evaluated in AML. We therefore compared outcomes between AYA with AML treated at pediatric vs. adult centers using a population-based clinical database. In addition, we determined other predictors of outcome within this population. Methods: The IMPACT Cohort comprises all Ontario, Canada AYA aged 15-21 years diagnosed with one of six common cancers (including AML) between 1992-2012. Detailed demographic, disease, treatment, and outcome data were collected through chart abstraction and validated by content experts. Locus of cancer care (LOC - pediatric vs. adult center) was determined based on where the majority of therapy was delivered in the first three months after diagnosis. Linkage to population-based health administrative data identified additional cancer events (second cancers, relapse, death). Event-free (EFS) and overall survival (OS) were determined using Kaplan-Meier methods. The impact of LOC on EFS and OS was determined using multivariable Cox proportional hazard models, adjusting for demographic, disease, and treatment variables. Events included disease progression, relapse, death, and second malignancies. Results: Among 140 AYA with AML, 89 (63.6%) received therapy at an adult center. AYA treated in pediatric centers were younger than those treated at adult centers (median 16 years vs. 19 years; p<0.001) and were more likely to live in higher-income neighborhoods [37/51 (72.5%) vs. 47/89 (52.8%); p=0.02]. Disease markers such as presenting white blood cell count and AML subtype did not differ by LOC. The 5-year EFS and OS for the whole cohort were 35.0%±4.0% and 53.6%±4.2%. Neither EFS nor OS differed by LOC (Table 1). In multivariable analyses adjusting for disease characteristics, LOC was not predictive of either EFS [adult vs. pediatric center hazard ratio (HR) 1.3, 95thconfidence interval (CI) 0.8-2.2, p=0.27] or OS (HR 1.0, CI 0.6-1.6, p=0.97). AYA with AML living in rural areas however experienced significantly inferior outcomes as compared to their urban counterparts (EFS: HR 2.5, CI 1.3-4.7, p=0.005; OS: HR 2.0, CI 1.1-3.8, p=0.04). Conclusions: In this population-based cohort, outcomes did not differ between AYA with AML treated at pediatric vs. adult centers, unlike what has been previously shown in AYA with acute lymphoblastic leukemia. However, rural AYA experienced substantially inferior outcomes than urban AYA, suggesting that even within a universal single payer system of healthcare, socioeconomic disparities persist in this population. Disclosures No relevant conflicts of interest to declare.

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 (22) ◽  
pp. 1564-1564 ◽  
Author(s):  
Hsin An Hou ◽  
Jih-Luh Tang ◽  
Liang-In Lin ◽  
Chien-Yuan Chen ◽  
Wen-Chien Chou ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Adult Patients ◽  
Poor Prognostic Factor ◽  
The Impact ◽  
Runx1 Mutation ◽  
Acute Myeloid

Abstract Abstract 1564 Poster Board I-587 Somatic mutation of AML1/RUNX1 (RUNX1) gene is seen in acute myeloid leukemia (AML) M0 subtype and 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 individuals (13.2%); 32 were in N-terminal and 31, C-terminal. The RUNX1 mutation was closely associated with male gender, older age, lower LDH value, FAB 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 (P=0.0061), but negatively associated with CEBPA (P=0.0057) and NPM1 mutations (P=0.0001). AML patients with RUNX1 mutations had a significantly lower complete remission rate, shorter disease-free and overall survival than those without the mutation (P=0.0087, P<0.0001 and P=0.012, respectively). Subgroup analysis of patients with normal karyotype showed that RUNX1-mutation was also closely associated with worse OS and DFS (P= 0.001 and P=0.001, respectively). Multivariate analysis demonstrated that RUNX1 mutation was an independent poor prognostic factor for overall survival (hazard ratio 1.874, 95% CI, 1.101- 3.189, P=0.021). Sequential analysis in 133 patients revealed that none acquired novel RUNX1 mutations during clinical courses. Our findings provide evidences that RUNX1 mutations are associated with distinct biological and clinical characteristics and poor prognosis in patients with de novo AML. Disclosures No relevant conflicts of interest to declare.

Roles of TET2 and C-CBL Mutations In the Progression of De Novo Myelodysplastic Syndrome to Acute Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4019-4019
Author(s):  
Hsiao-Wen Kao ◽  
Seishi Ogawa ◽  
Masashi Sanada ◽  
Der-Cherng Liang ◽  
Chang-Liang Lai ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Mutational Analysis ◽  
Conflicts Of Interest ◽  
Direct Sequencing ◽  
Increased Risk ◽  
The Impact ◽  
Acute Myeloid

Abstract Abstract 4019 Background. The molecular pathogenesis of myelodysplastic syndrome (MDS) and its role in the progression to secondary acute myeloid leukemia (sAML) remain to be further explored. Somatic TET2 and C-CBL mutations have recently been described in myeloid neoplasms including MDS and sAML. Most studies of TET2 or C-CBL mutations were carried out separately either at MDS or at sAML phases. There was also a discrepancy in the results of the impact of TET2 and C-CBL mutations on outcome of MDS patients. Aims. We aimed (1) to correlate the TET2 and C-CBL mutations with clinicohematological features and outcome, and (2) to determine the role of TET2 or C-CBL gene mutations in sAML derived from MDS. Materials and Methods. Bone marrow (BM) samples from 161 MDS patients (3 RCUD, 1 RARS, 36 RCMD, 118 RAEB, 1 MDS5q-, 2 MDS-U) at initial diagnosis were analyzed for both TET2 and C-CBL mutations; 49 of them had matched paired sAML BM samples available for comparative analysis. Mutational analysis was performed by DHPLC and/or direct sequencing of all RT-PCR or DNA-PCR products amplified with different primer pairs covering the whole coding sequences of TET2 and exons 7 to 9 of C-CBL. Results. The frequency of TET2 and C-CBL mutations in 161 MDS patients was 17.9 % and 1.9 %, respectively. Seven patients with polymorphism/germ line mutations or missense mutations outside of BOX 1 or 2 of TET2 gene were excluded. Of the 26 patients with 38 TET2 mutations, 14 had nonsense, 11 missense, 11 frameshift, 1 deletion, and 1 splice site mutations; 12 of them had double mutations. Three patients had C-CBL mutations (Y371S, F418S and G415S) at MDS phase. No patient had coexistence of TET2 and C-CBL mutations. TET2 mutations were significantly associated with increased risk of AML transformation (P= 0.037), whereas C-CBL mutations did not influence the risk of AML transformation (P=0.335). Patients carrying TET2 mutations had a trend of shorter time to sAML compared with those without TET2 mutations (estimated median time to sAML 8.7 months vs 15.0 months, P=0.067). Except for lower platelet count in patients with TET2 mutations (P=0.038), there were no significant differences in clinicohematological features including age, sex, hemoglobin level, white blood cell count, percentage of blasts in BM or peripheral blood, cytogenetics or IPSS (≤1.5 vs ≥2.0) between patients with and without TET2 or C-CBL mutations. No significant differences were found in overall survival with respect to mutation status of TET2 (P= 0.244) or C-CBL (P= 0.646). Of the 49 paired BM samples, 3 patients harboring C-CBL mutations at MDS phase retained the identical mutations and another 3 acquired C-CBL mutations (L370_Y371 ins L, L399V and C416W) during sAML evolution. There was an increased risk of acquiring C-CBL mutations during AML transformation (odds ratio=4.16, P=0.041), whereas TET2 mutation patterns remained unchanged and none acquired or lost TET2 mutations in sAML progression. Conclusions. Our results showed an increased risk of acquiring C-CBL mutations during sAML transformation. TET2 mutations played a role as an initial event in the development of MDS in a subset of patients and were associated with more frequent and rapid sAML evolution. Supported by grants NHRI-EX99-9711SI, NSC97-2314-B-182-011-MY3 and DOH99-TD-C-111-006. Disclosures: No relevant conflicts of interest to declare.

Impact on Acute Myeloid Leukemia Relapse in Granulocyte Colony Stimulating Factor Application: A Meta-Analysis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5169-5169
Author(s):  
Xiaoqin Feng ◽  
Chunfu Li
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Meta Analysis ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Significant Difference ◽  
The Impact ◽  
Stimulating Factor ◽  
Acute Myeloid

Abstract Objective: This meta-analysis evaluated the impact of granulocyte colony-stimulating factor (G-CSF) added to chemotherapy on treatment outcomes including survival and disease recurrence in patients with acute myeloid leukemia (AML). Methods: Medline, Cochrane, EMBASE,Google Scholar databases were searched until December 7, 2015 using the following search terms. Randomized control trials (RCTs), two-arm, and prospective studies that investigated patients with AML who underwent stem-cell transplantation were included. Results: The overall analysis revealed significant improvement in overall survival (OS) (pooled HR= 0.90; 95%CI, 0.83 to 0.98; P = 0.017) and disease free survival (DFS) (pooled HR = 0.85; 95% CI, 0.77 to 0.94; P = 0.002) for patients receiving G-CSF with chemotherapy. Among patients without prior AML treatment, there was significant improvement in DFS (pooled HR = 0.87; 95% CI, 0.77 to 0.98; P = 0.021) and reduction in incidence of relapse (pooled HR = 0.81; 95% CI, 0.68 to 0.96; P = 0.015) for those who received G-CSF. However, subgroup analyses found no significant difference between G-CSF (+) and G-CSF (-) treatments in rates of OS (P = 0.135) and complete remission (CR) (P = 0.357) for patients without prior AML treatment. Among patients with relapsed/refractory AML, there was no significant difference found between G-CSF(+) and G-CSF(-)groups for OS (P = 0.225), DFS (P = 0.209) and CR (P = 0.208).[EG1] Discussion and Co nclusion: Treatment with chemotherapy plus G-CSF appears to provide better survival and treatment responses compared with chemotherapy alone, particularly for patients with previously untreated AML. Disclosures No relevant conflicts of interest to declare.

scholarly journals Genome-Wide Mapping and Subtype Classification of Long Non-Coding RNA in Acute Myeloid Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2355-2355
Author(s):  
Rong Chen ◽  
Gabriel G Malouf ◽  
Jianping Zhang ◽  
Xuelin Huang ◽  
John N Weinstein ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Genetic Alterations ◽  
Cell Physiology ◽  
Fusion Transcripts ◽  
Subtype Classification ◽  
Genome Wide ◽  
Acute Myeloid

Abstract Background: Most efforts to characterize acute myeloid leukemia (AML) have focused so far on genetic and epigenetic aberrations, which can ultimately lead to altered protein-coding gene function. The roles of long non-coding RNAs (lncRNAs), which orchestrate cell physiology and act as key regulators of the AML oncogenic state, remain uncharacterized globally. Material and Methods: We performed a genomic analysis of GENCODE lncRNAs in 179 clinically annotated cases of de novo AML, using The Cancer Genome Atlas (TCGA) RNA-Seq data. In addition, we described global correlations between lncRNAs and the expression of cis- and trans-acting genes. We also established lncRNA-based subtype classification based on distinct signatures and then correlated that classification with fusion transcripts and genetic alterations. Results: Using stringent criteria (RPKM ≥1 in at least 10% of AML), we identified 2,913 expressed lncRNAs and used an integrative analysis to predict those that are potential regulators of AML oncogenic state. The expression of 1,935 (66.4%) lncRNAs showed positive correlations with the mRNA expression of their neighboring genes, while only 14 (0.4%) of the lncRNAs showed negative correlations. Gene ontology analysis using GREAT revealed enrichment of cis-neighboring genes in the PML body gene set (p=8.2x10-7). Unsupervised clustering of lncRNA-based expression showed five robust molecular clusters (C1 to C5), which were highly correlated with the mRNA-based classification. Of those, three clusters (C1, C2 and C5) were tightly associated with recurrent fusion transcripts; cluster C1 (n=16) was composed exclusively of promyelocytic leukemias, while cluster C5 (n=45) was enriched for MLL-rearranged cases (24.4%), and cluster C2 (n=31) was enriched for MYH11-CBFB or RUNX1-RUNX1T1 (55.2%) rearranged cases. Importantly, cluster C4 (n=30), which includes cytogenetically normal leukemias, was highly enriched for NPM1 (p=2.3x10-11) and FLT3 (p=1.6x10-4) mutations; conversely, cluster C3 (n=53) was highly enriched for recurrent copy-number alterations as well as RUNX1 (p=0.001) and TP53 somatic mutations (p=0.004). We further discovered a core of 37 lncRNAs significantly associated with a MLL-signature and 16 lncRNAs with a NPM1-mutated signature. Conclusion: This study describes the first genome-wide mapping and characterization of lncRNAs in AML and proposes a robust lncRNA-based classification. This classification may serve in defining core lncRNAs that orchestrate key oncogenic states in the different clinical subtypes. Disclosures No relevant conflicts of interest to declare.

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 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.

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