scholarly journals Studies of FLT3 mutations in paired presentation and relapse samples from patients with acute myeloid leukemia: implications for the role of FLT3 mutations in leukemogenesis, minimal residual disease detection, and possible therapy with FLT3 inhibitors

Blood ◽  
2002 ◽  
Vol 100 (7) ◽  
pp. 2393-2398 ◽  
Author(s):  
Panagiotis D. Kottaridis ◽  
Rosemary E. Gale ◽  
Stephen E. Langabeer ◽  
Marion E. Frew ◽  
David T. Bowen ◽  
...  

FLT3 mutations, either internal tandem duplications (ITDs) or aspartate residue 835 (D835) point mutations, are present in approximately one third of patients with acute myeloid leukemia (AML) and have been associated with an increased relapse rate. We have studied FLT3 mutations in paired presentation and relapse samples to ascertain the biology of these mutations and to evaluate whether they can be used as markers of minimal residual disease. At diagnosis, 24 patients were wild-type FLT3, and 4 acquired a FLT3 mutation at relapse (2 D835+, 2 ITD+), with a further patient acquiring an ITD at second relapse. Of 20 patients positive at diagnosis (18 ITD+, 2 D835+), 5 who were all originally ITD+ had no detectable mutation at relapse, as determined by a sensitive radioactive polymerase chain reaction. One of these patients had acquired an N-Ras mutation not detectable at presentation. Furthermore, another patient had a completely different ITD at relapse, which could not be detected in the presentation sample. These results indicate that FLT3 mutations are secondary events in leukemogenesis, are unstable, and thus should be used cautiously for the detection of minimal residual disease.

2018 ◽  
Vol 97 (7) ◽  
pp. 1155-1167 ◽  
Author(s):  
A. Coltoff ◽  
J. Houldsworth ◽  
A. Keyzner ◽  
A. S. Renteria ◽  
John Mascarenhas

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2016-2016
Author(s):  
Michela Palmisano ◽  
Tiziana Grafone ◽  
Emanuela Ottaviani ◽  
Nicoletta Testoni ◽  
Stefania Paolini ◽  
...  

Abstract Nucleophosmin (NPM) is a multifunctional phosphoprotein that acts as nucleocytoplasmic shuttling protein, with tumour suppressor and oncogenic functions. Recently, NPM mutations have been found in a subset of adults with de novo acute myeloid leukemia (AML). These mutations occur in the last coding exon (exon 12), causing a frameshift and the formation of novel C-termini. The abnormal mutated NPM protein shows aberrant cytoplasmic localization and is frequently associated with FLT3 mutation. These observations provide basis for studies of the pathogenesis in AML. We did sequential analysis on patient samples during the clinical course to investigate the stability and pathogenetic role of NPM mutation in AML and the association with FLT3 mutations. The NPM mutations were determined by D-HPLC analysis; samples exhibiting an abnormal D-HPLC profile were confirmed by direct sequencing. We investigated 28 patients of de novo AML. Eleven samples were sequenced since they showed an heteroduplex D-HPLC profile. Type A mutation (960_963dupTCTG) was the commonest observed change, occurring in 9/11 samples, followed by type B mutation (960_963insCATG) in 1 case and type D mutation (960_963insCCTG) in 1 case. Furthermore, we observed that 5/11 patients harboring NPM mutation presented also mutant FLT3 at diagnosis. Analyzing NPM mutations during progression of disease, we observed that NPM mutation disappeared at complete remission and the same mutation reappeared at relapse. No differences were found in wild type NPM. Instead, we found a modification of FLT3 status associated to evolution of disease in 7/28 patients: 2 patients lost the mutation at relapse, 4 patients acquired the mutation at relapse and 1 patient modified the mutation from D835 to ITD (Table 1). Together these results suggest that NPM mutations and not FLT3 mutations may have utility as a potential marker for monitoring minimal residual disease. Studies on the biological effects of NPM mutations will contribute to disclose the role of NPM mutations in the pathogenesis of AML and their interactions with other genetic alterations such as FLT3.


2019 ◽  
Vol 19 ◽  
pp. S235
Author(s):  
Nupur Das ◽  
Ankit Malhotra ◽  
Ritu Gupta ◽  
Sandeep Rai ◽  
Sanjeev k. Gupta ◽  
...  

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