Acute myeloid leukaemia with <i>FLT3</i> gene mutations of both internal tandem duplication and point mutation type

Chen, Weina; Jones, Dan; Medeiros, L. Jeffrey; Luthra, R.; Lin, Pei

doi:10.1111/j.1365-2141.2005.05666.x

Cited by 32 publications

(22 citation statements)

References 11 publications

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“…Whole or partial losses of chromosome 7 are rarely associated with ITD or ATKD. In fact, we know of only a handful AML cases, all in adults, with del(7q) or monosomy 7 together with a FLT3 mutation (Horiike et al, 1997;Kottaridis et al, 2001;Thiede et al, 2002;Side et al, 2004;Chen et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

FLT3 mutations in a 10 year consecutive series of 177 childhood acute leukemias and their impact on global gene expression patterns

Andersson

Paulsson

Lilljebjörn

et al. 2007

Genes Chromosomes & Cancer

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During 1995-2004, 209 children/adolescents were diagnosed with acute lymphoblastic or myeloid leukemia (ALL, AML) in Southern Sweden, of which 177 (85%), comprising 128 B-lineage ALL, 34 AML, and 15 T-cell ALL, could be analyzed for internal tandem duplications (ITD) and activating point mutations in the second tyrosine kinase domain (ATKD) of FLT3. Seventeen (10%) FLT3 mutations (6 ITD, 11 ATKD; mutually exclusive) were detected. None of the T-cell ALL harbored any mutations. ITD and ATKD were found in 2% and 6% of the B-lineage ALL and in 12% and 9% of the AML, being particularly common in high hyperdiploid ALL (14%), ALL (20%), and AML (23%) with 11q23/MLL rearrangements, and in AML with a normal karyotype (60%). All ATKD-positive AML with MLL rearrangements harbored the t(9;11)(p21;q23). Global gene expression data were available for 76 of the B-lineage ALL and 19 of the AML, of which 6 (8%) and 3 (16%) had FLT3 mutations, respectively. No distinct expression pattern associated with FLT3 mutations was identified.

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Section: Discussionmentioning

confidence: 99%

FLT3 mutations in a 10 year consecutive series of 177 childhood acute leukemias and their impact on global gene expression patterns

Andersson

Paulsson

Lilljebjörn

et al. 2007

Genes Chromosomes & Cancer

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“…FLT3 ITD and codon 835/838 TKD mutations were determined from genomic DNA extracted from bone marrow aspirate using a short-cycle PCR-based method, with subsequent restriction-digest with EcoRV for the TKD reaction and size fractionation by capillary electrophoresis, as described 39 . Quantification of mutation burden was performed by summing the area under the curve for all TKD or ITD peaks divided by the total peak areas for mutant and unmutated peaks.…”

Section: Methodsmentioning

confidence: 99%

Prognostic value of FLT3 mutations among different cytogenetic subgroups in acute myeloid leukemia

Santos

Jones

Qiao

et al. 2010

Cancer

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Background Impact of FLT3 mutations and mutation burden in cytogenetic subgroups of acute myeloid leukemia (AML) other than normal karyotype (NK-AML) is unclear. Methods Patients with newly diagnosed AML were divided among three cytogenetic subgroups: Core-Binding Factor (CBF) AML, NK-AML, Poor Risk AML. Results A total of 481 patients were included (CBF-AML – 13%, NK-AML – 57%, poor risk – 30%). FLT3 mutations (any) frequency was 20%, 32% and 7.6% in respective cytogenetic subgroups. FLT3 mutation did not impact event free survival (EFS) in patients with CBF (P=0.84) and poor-risk AML (P=0.37). In NK-AML, EFS was worse in the FLT3-internal tandem duplication (ITD) group (20 vs. 41 weeks, P<0.00001) but not in FLT3 tyrosine kinase domain (TKD) point mutation group (61 vs. 41 weeks, P=0.15). Patients with NK-AML and higher FLT3-ITD burden had worse EFS and overall survival (OS), but not so with FLT3-TKD mutation. In multivariate analysis, FLT3-ITD mutation was prognostic for EFS in NK-AML patients (hazard ratio 3.1, P=0.03). Conclusion FLT3 mutations did not have a prognostic impact in AML patients with good and poor-risk karyotype. In patients with NK-AML, FLT3-ITD mutations led to worse survival, more so in patients with high mutation burden.

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“…The FLT3 gene was assessed for ITD mutations using polymerase chain reaction (PCR) methods, as described previously 11 .…”

Section: Methodsmentioning

confidence: 99%

Cytoplasmic localization of nucleophosmin in bone marrow blasts of acute myeloid leukemia patients is not completely concordant with NPM1 mutation and is not predictive of prognosis

Konoplev

Huang

Drabkin

et al. 2009

Cancer

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Background NPM1 mutations are reported to predict a favorable prognosis in acute myeloid leukemia (AML) patients. Aberrant cytoplasmic localization of NPM protein is reported be a surrogate for NPM1 gene mutation. Methods Using immunohistochemical analysis (IHC), we assessed for NPM (clone 376) expression in formalin-fixed, formic acid-decalcified bone marrow biopsy specimens. DNA sequencing of the exon 12 of NPM1 gene was performed in 104 patients. Results The study included 252 AML patients: 192 de novo AML, 33 AML following a myelodysplastic syndrome or chronic myelomonocytic leukemia, and 27 therapy-related AML. The median age was 62 years and 115 patients were ≤ 60 years old. All patients received intensive chemotherapy. Cytoplasmic NPM was detected in 59 of 252 (23%) patients, including 48 of 192 (25%) de novo AML and 33 of 94 (35%) with a normal karyotype. DNA sequencing identified NPM1 mutations in 30 of 38 cases with cytoplasmic NPM and 10 of 66 cases with nuclear NPM. Cytoplasmic NPM was associated with young patient age (p=0.024), FLT3/ITD (p=0.005), CD34- negative blasts (p<0.001), high peripheral blood blast counts (p=0.041), and high serum albumin level (p=0.028). No statistical differences in overall or event-free survival were found on the basis of NPM localization. Similar results were obtained in patients ≤ 60 years old with normal karyotype and wild-type FLT3 (p=0.768). Conclusions Immunohistochemical assessment for NPM localization did not predict prognosis in this patient cohort. The discordance between immunohistochemistry and DNA sequencing results indicates that DNA sequencing cannot be replaced by IHC assessment.

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Acute myeloid leukaemia with FLT3 gene mutations of both internal tandem duplication and point mutation type

Cited by 32 publications

References 11 publications

FLT3 mutations in a 10 year consecutive series of 177 childhood acute leukemias and their impact on global gene expression patterns

FLT3 mutations in a 10 year consecutive series of 177 childhood acute leukemias and their impact on global gene expression patterns

Prognostic value of FLT3 mutations among different cytogenetic subgroups in acute myeloid leukemia

Cytoplasmic localization of nucleophosmin in bone marrow blasts of acute myeloid leukemia patients is not completely concordant with NPM1 mutation and is not predictive of prognosis

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