TY - JOUR
T1 - FLT3-ITD mutations in acute myeloid leukaemia – molecular characteristics, distribution and numerical variation
AU - Engen, Caroline
AU - Hellesøy, Monica
AU - Grob, Tim
AU - Al Hinai, Adil
AU - Brendehaug, Atle
AU - Wergeland, Line
AU - Bedringaas, Siv Lise
AU - Hovland, Randi
AU - Valk, Peter J.M.
AU - Gjertsen, Bjørn T.
N1 - Funding Information:
Grants supporting this work were provided by The Research Council of Norway, Helse Vest health trust and the Norwegian Cancer Society. Study design, data analysis, interpretation of results and preparation of the manuscript were performed without involvement of funding bodies. The authors are grateful to the patients that participated in the respective HOVON/SAKK trials. We further thank personnel at the Gjertsen laboratory and Valk laboratory for contributing with technical assistance. This study was supported by funding from the Norwegian Cancer Society with Solveig & Ole Lunds Legacy, ?yvinn M?lbach-Petersens Fund for Clinical Research and grant no 303445. Additionally, the study was funded through Helse Vest HF Health Trust, Grant Numbers: 911809, 911852, 912171, 240222 and 912308.
Funding Information:
Grants supporting this work were provided by The Research Council of Norway, Helse Vest health trust and the Norwegian Cancer Society. Study design, data analysis, interpretation of results and preparation of the manuscript were performed without involvement of funding bodies. The authors are grateful to the patients that participated in the respective HOVON/SAKK trials. We further thank personnel at the Gjertsen laboratory and Valk laboratory for contributing with technical assistance. This study was supported by funding from the Norwegian Cancer Society with Solveig & Ole Lunds Legacy, Øyvinn Mølbach‐Petersens Fund for Clinical Research and grant no 303445. Additionally, the study was funded through Helse Vest HF Health Trust, Grant Numbers: 911809, 911852, 912171, 240222 and 912308.
Publisher Copyright:
© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies
PY - 2021/9/1
Y1 - 2021/9/1
N2 - Recurrent somatic internal tandem duplications (ITD) in the FMS-like tyrosine kinase 3 (FLT3) gene characterise approximately one third of patients with acute myeloid leukaemia (AML), and FLT3-ITD mutation status guides risk-adapted treatment strategies. The aim of this work was to characterise FLT3-ITD variant distribution in relation to molecular and clinical features, and overall survival in adult AML patients. We performed two parallel retrospective cohort studies investigating FLT3-ITD length and expression by cDNA fragment analysis, followed by Sanger sequencing in a subset of samples. In the two cohorts, a total of 139 and 172 mutant alleles were identified in 111 and 123 patients, respectively, with 22% and 28% of patients presenting with more than one mutated allele. Further, 15% and 32% of samples had a FLT3-ITD total variant allele frequency (VAF) < 0.3, while 24% and 16% had a total VAF ≥ 0.7. Most of the assessed clinical features did not significantly correlate to FLT3-ITD numerical variation nor VAF. Low VAF was, however, associated with lower white blood cell count, while increasing VAF correlated with inferior overall survival in one of the cohorts. In the other cohort, ITD length above 50 bp was identified to correlate with inferior overall survival. Our report corroborates the poor prognostic association with high FLT3-ITD disease burden, as well as extensive inter- and intrapatient heterogeneity in the molecular features of FLT3-ITD. We suggest that future use of FLT3-targeted therapy could be accompanied with thorough molecular diagnostics and follow-up to better predict optimal therapy responders.
AB - Recurrent somatic internal tandem duplications (ITD) in the FMS-like tyrosine kinase 3 (FLT3) gene characterise approximately one third of patients with acute myeloid leukaemia (AML), and FLT3-ITD mutation status guides risk-adapted treatment strategies. The aim of this work was to characterise FLT3-ITD variant distribution in relation to molecular and clinical features, and overall survival in adult AML patients. We performed two parallel retrospective cohort studies investigating FLT3-ITD length and expression by cDNA fragment analysis, followed by Sanger sequencing in a subset of samples. In the two cohorts, a total of 139 and 172 mutant alleles were identified in 111 and 123 patients, respectively, with 22% and 28% of patients presenting with more than one mutated allele. Further, 15% and 32% of samples had a FLT3-ITD total variant allele frequency (VAF) < 0.3, while 24% and 16% had a total VAF ≥ 0.7. Most of the assessed clinical features did not significantly correlate to FLT3-ITD numerical variation nor VAF. Low VAF was, however, associated with lower white blood cell count, while increasing VAF correlated with inferior overall survival in one of the cohorts. In the other cohort, ITD length above 50 bp was identified to correlate with inferior overall survival. Our report corroborates the poor prognostic association with high FLT3-ITD disease burden, as well as extensive inter- and intrapatient heterogeneity in the molecular features of FLT3-ITD. We suggest that future use of FLT3-targeted therapy could be accompanied with thorough molecular diagnostics and follow-up to better predict optimal therapy responders.
UR - http://www.scopus.com/inward/record.url?scp=85104718814&partnerID=8YFLogxK
U2 - 10.1002/1878-0261.12961
DO - 10.1002/1878-0261.12961
M3 - Article
C2 - 33817952
AN - SCOPUS:85104718814
VL - 15
SP - 2300
EP - 2317
JO - Molecular Oncology
JF - Molecular Oncology
SN - 1574-7891
IS - 9
ER -
