The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia

Gale, Rosemary E.; Green, Claire; Allen, Christopher; Mead, Adam J.; Burnett, Alan Kenneth; Hills, Robert Kerrin; Linch, David C.

doi:10.1182/blood-2007-08-109090

Cited by 663 publications

(639 citation statements)

References 33 publications

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“…[17][18][19][20][21] More recently, increasing evidence suggests that higher FLT3-ITD to wild-type allelic ratios are associated with poor prognosis. 22 In our patients, FLT3 mutation by itself did not impact DFS. When FLT3-ITD and ABCG2 overexpression occurred together, outcome was significantly worsened with a shorter DFS in double-positive patients.…”

Section: Discussionmentioning

confidence: 46%

Concomitant ABCG2 overexpression and FLT3‐ITD mutation identify a subset of acute myeloid leukemia patients at high risk of relapse

Tiribelli¹,

Geromin²,

Michelutti³

et al. 2010

Cancer

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BACKGROUND: ABCG2 protein overexpression and FLT3 internal tandem duplication (ITD) correlate with higher relapse rate and shorter disease-free survival (DFS) in acute myeloid leukemia (AML), but no data are available on the possible effect of concomitant presence of these 2 factors. METHODS: The authors analyzed the outcome of 166 cases of adult AML patients who were homogeneously treated with a fludarabine-based induction therapy. RESULTS: ABCG2 overexpression and FLT3-ITD were detected in 83 (50%) and 47 (28%) patients, respectively. A significant correlation was found between ABCG2 positivity and FLT3 mutation, with 33 (40%) ITD in 83 ABCG2-positive patients compared with 14 (17%) ITD in 83 ABCG2-negative patients (P ¼ .002). Complete remission (CR) after induction therapy was achieved in 95 (57%) patients. Neither ABCG2 overexpression nor FLT3-ITD had any impact on achievement of CR. Relapse occurred in 42 of 95 (44%) patients at a median time of 28 months. Time to relapse was shortened in patients overexpressing ABCG2 (P ¼ .0004). DFS was not affected by FLT3-ITD alone, but FLT3 mutation significantly worsened long-term outcome of ABCG2-positive patients. DFS at 1 and 3 years in patients with overexpression of both ABCG2 and FLT3-ITD was only 36% and 28%, respectively; in ABCG2-positive/FLT3-negative patients, DFS at 1 and 3 years was 65% and 48%, respectively; and in ABCG2-negative cases (regardless of FLT3 status), DFS at 1 and 3 years was greater than 85% and 75%. CONCLUSIONS: Concomitant overexpression of ABCG2 and FLT3-ITD is relatively frequent and identifies a subgroup of AML patients with a significantly worse prognosis. The possible interactions between these 2 prognostic factors need to be defined. Cancer 2011;117:2156-62.

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Section: Discussionmentioning

confidence: 46%

Concomitant ABCG2 overexpression and FLT3‐ITD mutation identify a subset of acute myeloid leukemia patients at high risk of relapse

Tiribelli¹,

Geromin²,

Michelutti³

et al. 2010

Cancer

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“…These observations point to the interesting possibility that different populations of malignant cells (which are represented by different cell lines) use distinct mechanisms for activating NF-kB. There is a considerable heterogeneity in the response of AML patients to Flt3 inhibitors (Yanada et al, 2005;Knapper, 2007;Gale et al, 2008) or ATMIs (this study), and it will be important to assess the combined proapoptotic effect of kinase inhibitors affecting Flt3 and ATM on preclinical models of AML in the future. Preliminary data obtained with purified CD34 þ BM cells from a limited number of patients suggest that there are two different groups of patients, one group whose marrow blasts respond preferentially to ATMIs and another group that preferentially responds to Flt3 inhibitors.…”

Section: Discussionmentioning

confidence: 88%

ATM mediates constitutive NF-κB activation in high-risk myelodysplastic syndrome and acute myeloid leukemia

et al. 2008

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The anti-apoptotic transcription factor nuclear factor-jB (NF-jB) is constitutively activated in CD34 þ myeloblasts from high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients. Inhibition of NF-jB by suppressing the canonical NF-jB activation pathway, for instance by knockdown of the three subunits of the inhibitor of NF-jB (IjB) kinase (IKK) complex (IKK1, IKK2 and NEMO) triggers apoptosis in such cells. Here, we show that an MDS/AML model cell line exhibits a constitutive interaction, within the nucleus, of activated, S1981-phosphorylated ataxia telangiectasia mutated (ATM) with NEMO. Inhibition of ATM with two distinct pharmacological inhibitors suppressed the activating autophosphorylation of ATM, blocked the interaction of ATM and NEMO, delocalized NEMO as well as another putative NF-jB activator, PIDD, from the nucleus, abolished the activating phosphorylation of the catalytic proteins of the IKK complex (IKK1/2 on serines 176/180), enhanced the expression of IjBa and caused the relocalization of NF-jB from the nucleus to the cytoplasm, followed by apoptosis. Knockdown of ATM with small-interfering RNAs had a similar effect that could not be enhanced by knockdown of NEMO, PIDD and the p65 NF-jB subunit, suggesting that an ATM inhibition/ depletion truly induced apoptosis through inhibition of the NF-jB system. Pharmacological inhibition of ATM also induced the nucleocytoplasmic relocalization of p65 in malignant myeloblasts purified from patients with highrisk MDS or AML, correlating with the induction of apoptosis. Altogether, these results support the contention that constitutively active ATM accounts for the activation of NF-jB in high-risk MDS and AML.

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“…It is interesting to note that , a recent large study of the Medical Research Council in adult CN-AML also reported a positive effect of NPM1 mutations in the FLT3/ITD-positive group, irrespective of the FLT3/ITD AR. 35 We did not identify differences in the characteristics of FLT3/ITD, that is, AR or ITD length, that could explain why FLT3/ITD did not have a prognostic influence in our NPM1-mutated patients. In addition, SCT could not explain the difference in impact; only a small number of our patients were transplanted, and there were no significant differences in the number of patients transplanted in the various subgroups.…”

Section: Discussionmentioning

confidence: 99%

Favorable prognostic impact of NPM1 gene mutations in childhood acute myeloid leukemia, with emphasis on cytogenetically normal AML

Hollink

Zwaan

Zimmermann³

et al. 2008

Leukemia

150

121

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Nucleophosmin (NPM1) mutations occur frequently in adult cytogenetically normal acute myeloid leukemia (CN-AML) and confer favorable outcome. We investigated the frequency and prognostic significance of NPM1 mutations in childhood AML (n ¼ 298), specifically focusing on the CN-AML subgroup (n ¼ 100). Mutations were found in 8.4%, and clustered significantly in the CN-AML subgroup (22%). No mutations were found in patients below the age of 3 years; in CN-AML, there was an increasing incidence above this age. In the overall group, NPM1 mutations conferred an independent favorable prognostic impact on event-free survival (5-year pEFS 66 vs 39%; P ¼ 0.02), which did not translate into a significantly better overall survival (5-year pOS 68 vs 56%; P ¼ 0.30). However, when the favorable cytogenetic subgroups [inv(16) and t(8;21)] were excluded from the NPM1 wild-type group, the difference in pOS was borderline statistically significant (68 vs 45%; P ¼ 0.07). In the CN-AML cohort, NPM1 mutations were an independent prognostic factor on pEFS (80 vs 39%; P ¼ 0.01), and pOS (85 vs 60%; P ¼ 0.06), which was not influenced by FLT3/ITD. However, in NPM1 wild-type CN-AML, FLT3/ITDpositive patients had a significantly worse outcome (pEFS 48 vs 18%; Po0.001). We conclude that NPM1 mutations confer a favorable prognosis in childhood AML and in CN-AML in particular.

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The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia

Cited by 663 publications

References 33 publications

Concomitant ABCG2 overexpression and FLT3‐ITD mutation identify a subset of acute myeloid leukemia patients at high risk of relapse

Concomitant ABCG2 overexpression and FLT3‐ITD mutation identify a subset of acute myeloid leukemia patients at high risk of relapse

ATM mediates constitutive NF-κB activation in high-risk myelodysplastic syndrome and acute myeloid leukemia

Favorable prognostic impact of NPM1 gene mutations in childhood acute myeloid leukemia, with emphasis on cytogenetically normal AML

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