Dataset Information

Frugal alignment-free identification of FLT3-internal tandem duplications with FiLT3r.

ABSTRACT:

Background

Internal tandem duplications in the FLT3 gene, termed FLT3-ITDs, are useful molecular markers in acute myeloid leukemia (AML) for patient risk stratification and follow-up. FLT3-ITDs are increasingly screened through high-throughput sequencing (HTS) raising the need for robust and efficient algorithms. We developed a new algorithm, which performs no alignment and uses little resources, to identify and quantify FLT3-ITDs in HTS data.

Results

Our algorithm (FiLT3r) focuses on the k-mers from reads covering FLT3 exons 14 and 15. We show that those k-mers bring enough information to accurately detect, determine the length and quantify FLT3-ITD duplications. We compare the performances of FiLT3r to state-of-the-art alternatives and to fragment analysis, the gold standard method, on a cohort of 185 AML patients sequenced with capture-based HTS. On this dataset FiLT3r is more precise (no false positive nor false negative) than the other software evaluated. We also assess the software on public RNA-Seq data, which confirms the previous results and shows that FiLT3r requires little resources compared to other software.

Conclusion

FiLT3r is a free software available at https://gitlab.univ-lille.fr/filt3r/filt3r . The repository also contains a Snakefile to reproduce our experiments. We show that FiLT3r detects FLT3-ITDs better than other software while using less memory and time.

SUBMITTER: Boudry A

PROVIDER: S-EPMC9617311 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Publications

Frugal alignment-free identification of FLT3-internal tandem duplications with FiLT3r.

Boudry Augustin A Darmon Sasha S Duployez Nicolas N Figeac Martin M Geffroy Sandrine S Bucci Maxime M Celli-Lebras Karine K Duchmann Matthieu M Joudinaud Romane R Fenwarth Laurène L Nibourel Olivier O Goursaud Laure L Itzykson Raphael R Dombret Hervé H Hunault Mathilde M Preudhomme Claude C Salson Mikaël M

BMC bioinformatics 20221028 1

<h4>Background</h4>Internal tandem duplications in the FLT3 gene, termed FLT3-ITDs, are useful molecular markers in acute myeloid leukemia (AML) for patient risk stratification and follow-up. FLT3-ITDs are increasingly screened through high-throughput sequencing (HTS) raising the need for robust and efficient algorithms. We developed a new algorithm, which performs no alignment and uses little resources, to identify and quantify FLT3-ITDs in HTS data.<h4>Results</h4>Our algorithm (FiLT3r) focuse ...[more]

PMID: 36307762

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Project description:Activating internal tandem duplications (ITD) in the juxtamembrane domain of receptor tyrosine kinase FLT3 occur frequently in patients with acute myeloid leukemia (AML). Constitutive active FLT3-ITD mutations induce aberrant signaling and promote leukemic cell transformation. Inactivation of the attenuating receptor protein tyrosine phosphatase CD45 (PTPRC) in FLT3-ITD mice resulted in the development of a severe hematopoietic phenotype with characteristics of AML. In addition, abnormal bone structures and ectopic bone formation were observed in these mice, suggesting a previously unknown role of FLT3 to control bone development and remodeling. While Ptprc knockout and Flt3-ITD mutant mice showed a largely normal bone microarchitecture, micro-CT analysis of femurs from Flt3-ITD Ptprc knockout mice revealed trabecularization of the cortical bone. This resulted in increased trabecular bone volume at the metaphysis, while the cortical bone at the diaphysis was thinner and less dense. In the metaphysis, severely reduced osteoclast and osteoblast numbers were observed. Reduced capacity of ex vivo differentiation of CD11b-positive bone marrow stem cells to mature osteoclast was accompanied by their abnormal morphology and reduced size. Transcriptome analysis revealed reduced expression of osteoclastogenic genes. Unexpectedly, cumulative resorption activity of osteoclasts was increased. Size and structure of resorption pits of differentiated osteoclasts remained similar to those observed in osteoclast cultures derived from control animals. Enhanced proliferation of cells in osteoclast cultures derived from FLT3-ITD-expressing mice was mediated by increased expression of STAT5 target genes. Transcriptome analysis of differentiated osteoclasts showed dysregulated signaling pathways influencing their differentiation as well as the coupling of bone resorption and formation. Taken together, inactivation of attenuating CD45 in mice expressing oncogenic FLT3-ITD resulted in marked abnormalities of the osteo-hematopoietic niche, which can be explained by aberrant STAT5 activation.

Project description:We conducted a single-arm, phase 2 trial (German-Austrian Acute Myeloid Leukemia Study Group [AMLSG] 16-10) to evaluate midostaurin with intensive chemotherapy followed by allogeneic hematopoietic-cell transplantation (HCT) and a 1-year midosta urin maintenance therapy in adult patients with acute myeloid leukemia (AML) and fms-related tyrosine kinase 3 (FLT3) internal tandem duplication (ITD). Patients 18 to 70 years of age with newly diagnosed FLT3-ITD-positive AML were eligible. Primary and key secondary endpoints were event-free survival (EFS) and overall survival (OS). Results were compared with a historical cohort of 415 patients treated on 5 prior AMLSG trials; statistical analysis was performed using a double-robust adjustment with propensity score weighting and covariate adjustment. Results were also compared with patients (18-59 years) treated on the placebo arm of the Cancer and Leukemia Group B (CALGB) 10603/RATIFY trial. The trial accrued 440 patients (18-60 years, n = 312; 61-70 years, n = 128). In multivariate analysis, EFS was significantly in favor of patients treated within the AMLSG 16-10 trial compared with the AMLSG control (hazard ratio [HR], 0.55; P < .001); both in younger (HR, 0.59; P < .001) and older patients (HR, 0.42; P < .001). Multivariate analysis also showed a significant beneficial effect on OS compared with the AMLSG control (HR, 0.57; P < .001) as well as to the CALGB 10603/RATIFY trial (HR, 0.71; P = .005). The treatment effect of midostaurin remained significant in sensitivity analysis including allogeneic HCT as a time-dependent covariate. Addition of midostaurin to chemotherapy was safe in younger and older patients. In comparison with historical controls, the addition of midostaurin to intensive therapy led to a significant improvement in outcome in younger and older patients with AML and FLT3-ITD. This trial is registered at clinicaltrialsregistry.eu as Eudra-CT number 2011-003168-63 and at clinicaltrials.gov as NCT01477606.

Dataset Information

Frugal alignment-free identification of FLT3-internal tandem duplications with FiLT3r.

Background

Results

Conclusion

Publications

Frugal alignment-free identification of FLT3-internal tandem duplications with FiLT3r.

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