Trisomy 13 is strongly associated with AML1/RUNX1 mutations and increased FLT3 expression in acute myeloid leukemia

Blood ◽  
2007 ◽  
Vol 110 (4) ◽  
pp. 1308-1316 ◽  
Author(s):  
Frank Dicker ◽  
Claudia Haferlach ◽  
Wolfgang Kern ◽  
Torsten Haferlach ◽  
Susanne Schnittger
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Somatic Mutations ◽  
Fold Increase ◽  
Fusion Transcript ◽  
Trisomy 13 ◽  
Transcript Levels ◽  
High Incidence ◽  
Flt3 Mutations ◽  
Acute Myeloid

AbstractAML1/RUNX1 is implicated in leukemogenesis on the basis of the AML1-ETO fusion transcript as well as somatic mutations in its DNA-binding domain. Somatic mutations in RUNX1 are preferentially detected in acute myeloid leukemia (AML) M0, myeloid malignancies with acquired trisomy 21, and certain myelodysplastic syndrome (MDS) cases. By correlating the presence of RUNX1 mutations with cytogenetic and molecular aberration in a large cohort of AML M0 (N = 90) at diagnosis, we detected RUNX1 mutations in 46% of cases, with all trisomy 13 cases (n = 18) being affected. No mutations of NRAS or KIT were detected in the RUNX1-mutated group and FLT3 mutations were equally distributed between RUNX1-mutated and unmutated samples. Likewise, a high incidence of RUNX1 mutations (80%) was detected in cases with trisomy 13 from other French-American-British (FAB) subgroups (n = 20). As FLT3 is localized on chromosome 13, we hypothesized that RUNX1 mutations might cooperate with trisomy 13 in leukemogenesis by increasing FLT3 transcript levels. Quantitation of FLT3 transcript levels revealed a highly significant (P < .001) about 5-fold increase in AML with RUNX1 mutations and trisomy 13 compared with samples without trisomy 13. The results of the present study indicate that in the absence of FLT3 mutations, FLT3 overexpression might be a mechanism for FLT3 activation, which cooperates with RUNX1 mutations in leukemogenesis.

FLT3 mutations have no prognostic impact in elderly patients with acute myeloid leukemia and normal karyotype

2009 ◽  
Vol 84 (8) ◽  
pp. 532-534 ◽  
Author(s):  
Felicetto Ferrara ◽  
Clelia Criscuolo ◽  
Cira Riccardi ◽  
Tiziana Izzo ◽  
Mariangela Pedata ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Elderly Patients ◽  
Myeloid Leukemia ◽  
Normal Karyotype ◽  
Prognostic Impact ◽  
Flt3 Mutations ◽  
Acute Myeloid

scholarly journals Alternative splicing redefines landscape of commonly mutated genes in acute myeloid leukemia

2020 ◽  
Author(s):  
Osvaldo D. Rivera ◽  
Michael J. Mallory ◽  
Mathieu Quesnel-Vallières ◽  
David C. Schultz ◽  
Martin Carroll ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Alternative Splicing ◽  
Myeloid Leukemia ◽  
Gene Disruption ◽  
Somatic Mutations ◽  
Aberrant Splicing ◽  
Gene Dysregulation ◽  
Number Of Patients ◽  
Acute Myeloid ◽  
Classical Mutation

AbstractMost genes associated with Acute Myeloid Leukemia (AML) are mutated in less than 10% of patients, suggesting alternative mechanisms for gene disruption contribute to this disease. Here we find a set of splicing events that disrupt the expression of a subset of AML-associated genes, including EZH2 and ZRSR2, independent of known somatic mutations. Most strikingly, in at least one cohort, aberrant splicing triples the number of patients with a reduction in functional EZH2 as compared to that predicted by somatic mutation of EZH2 alone. Together, these results demonstrate that classical mutation analysis underestimates the burden of functional gene disruption in AML and highlights the importance of assessing the contribution of alternative splicing to gene dysregulation in human disease.

scholarly journals A Predictor Combining Clinical and Genetic Factors for AML1-ETO Leukemia Patients

2022 ◽  
Vol 11 ◽  
Author(s):  
Min Yang ◽  
Bide Zhao ◽  
Jinghan Wang ◽  
Yi Zhang ◽  
Chao Hu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Somatic Mutations ◽  
Genetic Factors ◽  
Risk Model ◽  
Core Binding Factor ◽  
Kit Mutation ◽  
Binding Factor ◽  
Prognostic Prediction ◽  
Acute Myeloid

Core Binding Factor (CBF)-AML is one of the most common somatic mutations in acute myeloid leukemia (AML). t(8;21)/AML1-ETO-positive acute myeloid leukemia accounts for 5-10% of all AMLs. In this study, we consecutively included 254 AML1-ETO patients diagnosed and treated at our institute from December 2009 to March 2020, and evaluated molecular mutations by 185-gene NGS platform to explore genetic co-occurrences with clinical outcomes. Our results showed that high KIT VAF(≥15%) correlated with shortened overall survival compared to other cases with no KIT mutation (3-year OS rate 26.6% vs 59.0% vs 69.6%, HR 1.50, 95%CI 0.78-2.89, P=0.0005). However, no difference was found in patients’ OS whether they have KIT mutation in two or three sites. Additionally, we constructed a risk model by combining clinical and molecular factors; this model was validated in other independent cohorts. In summary, our study showed that c-kit other than any other mutations would influence the OS in AML1-ETO patients. A proposed predictor combining both clinical and genetic factors is applicable to prognostic prediction in AML1-ETO patients.

scholarly journals Genome-wide CRISPR screen identifies regulators of MAPK and MTOR pathways mediating sorafenib resistance in acute myeloid leukemia

Haematologica ◽  
2020 ◽  
Author(s):  
Alisa Damnernsawad ◽  
Daniel Bottomly ◽  
Stephen E. Kurtz ◽  
Christopher A. Eide ◽  
Shannon K. McWeeney ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Ex Vivo ◽  
Mek Inhibitors ◽  
Genome Wide ◽  
A Genome ◽  
Flt3 Mutations ◽  
Flt3 Inhibitors ◽  
Crispr Screen ◽  
Acute Myeloid

Drug resistance impedes the long-term effect of targeted therapies in acute myeloid leukemia (AML), necessitating the identification of mechanisms underlying resistance. Approximately 25% of AML patients carry FLT3 mutations and develop post-treatment insensitivity to FLT3 inhibitors, including sorafenib. Using a genome-wide CRISPR screen, we identified LZTR1, NF1, TSC1 or TSC2, negative regulators of the MAPK and MTOR pathways, as mediators of sorafenib resistance. Analyses of ex vivo drug sensitivity assays in FLT3-ITD AML patient samples revealed lower expression of LZTR1, NF1, and TSC2 correlated with sorafenib sensitivity. Importantly, MAPK and/or MTOR complex1 (MTORC1) activity were upregulated in AML cells made resistant to several FLT3 inhibitors, including crenolanib, quizartinib, or sorafenib. These cells were sensitive to MEK inhibitors, and the combination of FLT3 and MEK inhibitors showed enhanced efficacy, suggesting its effectiveness in AML patients with FLT3 mutations and those with resistance to FLT3 inhibitors.

scholarly journals Pan-RAF Inhibition Shows Anti-Leukemic Activity in RAS-Mutant Acute Myeloid Leukemia Cells and Potentiates the Effect of Sorafenib in Cells with FLT3 Mutation

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3511
Author(s):  
Joseph D. Khoury ◽  
Mehrnoosh Tashakori ◽  
Hong Yang ◽  
Sanam Loghavi ◽  
Ying Wang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Signaling ◽  
Myeloid Leukemia ◽  
Critical Role ◽  
Cyclin B1 ◽  
Leukemic Cells ◽  
Phase Array ◽  
Flt3 Mutations ◽  
The Impact ◽  
Acute Myeloid

RAF molecules play a critical role in cell signaling through their integral impact on the RAS/RAF/MEK/ERK signaling pathway, which is constitutively activated in a sizeable subset of acute myeloid leukemia (AML) patients. We evaluated the impact of pan-RAF inhibition using LY3009120 in AML cells harboring mutations upstream and downstream of RAF. LY3009120 had anti-proliferative and pro-apoptotic effects and suppressed pERK1/2 levels in leukemic cells with RAS and FLT3 mutations. Using reverse protein phase array analysis, we identified reductions in the expression/activation of cell signaling components downstream of RAF (activated p38) and cell cycle regulators (Wee1/cyclin B1, Cdc2/Cdk1, activated Rb, etc.). Notably, LY3009120 potentiated the effect of Ara-C on AML cells and overcame bone marrow mesenchymal stromal cell-mediated chemoresistance, with RAS-mutated cells showing a notable reduction in pAKT (Ser473). Furthermore, the combination of LY3009120 and sorafenib resulted in significantly higher levels of apoptosis in AML cells with heterozygous and hemizygous FLT3 mutations. In conclusion, pan-RAF inhibition in AML using LY3009120 results in anti-leukemic activity, and combination with Ara-C or sorafenib potentiates its effect.

scholarly journals Clinical Outcomes and Persistence of Somatic Mutations in Acute Myeloid Leukemia Patients after Transplantation

2019 ◽  
Vol 25 (3) ◽  
pp. S105-S106
Author(s):  
Ayman Qasrawi ◽  
Zin Myint ◽  
Rani Jayswal ◽  
Ranjana Arora ◽  
Hayder Saeed ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Clinical Outcomes ◽  
Myeloid Leukemia ◽  
Somatic Mutations ◽  
Acute Myeloid

Recent advances in FLT3 inhibitors for acute myeloid leukemia

2020 ◽  
Vol 12 (10) ◽  
pp. 961-981 ◽  
Author(s):  
Lexian Tong ◽  
Xuemei Li ◽  
Yongzhou Hu ◽  
Tao Liu
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Clinical Stage ◽  
Wild Type ◽  
New Techniques ◽  
Flt3 Mutations ◽  
Flt3 Inhibitors ◽  
Target Activity ◽  
Acute Myeloid

Fms-like tyrosine kinase-3 (FLT3) mutations occur in approximately 30% of acute myeloid leukemia (AML) cases, suggesting FLT3 as an attractive target for AML treatment. Early FLT3 inhibitors enhance antileukemia efficacy by inhibiting multiple targets, and thus had stronger off-target activity, increasing their toxicity. Recently, a number of potent and selective FLT3 inhibitors have been developed, many of which are effective against multiple mutations. This review outlines the evolution of AML-targeting FLT3 inhibitors by focusing on their chemotypes, selectivity and activity over FLT3 wild-type and FLT3 mutations as well as new techniques related to FLT3. Compounds that currently enter the late clinical stage or have entered the market are also briefly reported.

scholarly journals Cytogenetic profile of minimally differentiated (FAB M0) acute myeloid leukemia: correlation with clinicobiologic findings [see comments]

Blood ◽  
1995 ◽  
Vol 85 (12) ◽  
pp. 3688-3694 ◽  
Author(s):  
A Cuneo ◽  
A Ferrant ◽  
JL Michaux ◽  
M Boogaerts ◽  
H Demuynck ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Normal Karyotype ◽  
Clinical Findings ◽  
Trisomy 13 ◽  
Professional Exposure ◽  
Cytogenetic Profile ◽  
Acute Myeloid ◽  
Clonal Abnormalities

Cytogenetic data were studied in 26 patients with de novo acute myeloid leukemia (AML) with minimal myeloid differentiation, corresponding to the M0 subtype of the French-American-British classification, in correlation with cytoimmunologic and clinical findings. Clonal abnormalities were detected in 21 cases (80.7%), 12 of which had a complex karyotype. Partial or total monosomy 5q and/or 7q was found, either as the sole aberration or in all abnormal metaphases, in 11 patients; in 8 cases, additional chromosome changes were present, including rearrangements involving 12p12–13 and 2p12–15 seen in 3 cases each. Five patients had trisomy 13 as a possible primary chromosome change; in 5 cases, nonrecurrent chromsome abnormalities were observed. Comparison of these findings with chromosome data from 42 patients with AML-M1 shows that abnormal karyotypes, complex karyotypes, unbalanced chromosome changes (-5/5q- and/or -7/7q- and +13) were observed much more frequently in AML-M0 than in AML-M1. Patients with abnormalities of chromosome 5 and/or 7 frequently showed trilineage myelodysplasia and low white blood cell count. Despite their relatively young age, complete remission was achieved in 4 of 11 patients only. Patients with +13 were elderly males with frequent professional exposure to myelotoxic agents. Unlike patients with clonal abnormalities, most AML-M0 patients with normal karyotype showed 1% to 2% peroxidase-positive blast cells at light microscopy and frequently achieved CR. It is concluded that (1) AML-M0 shows a distinct cytogenetic profile, partially recalling that of therapy-related AML, (2) different cytogenetic groups of AML-M0 can be identified showing characteristic clinicobiologic features, and (3) chromosome rearrangements may partially account for the unfavorable outcome frequently observed in these patients.

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