Co-occurrence of FLT3-TKD and NPM1 mutations defines a highly favorable prognostic AML group

Boddu, Prajwal; Kantarjian, Hagop M.; Borthakur, Gautam; Kadia, Tapan M.; Daver, Naval; Pierce, Sherry; Andreeff, Michael; Ravandi, Farhad; Cortes, Jorge; Kornblau, Steven M.

doi:10.1182/bloodadvances.2017009019

Cited by 58 publications

(37 citation statements)

References 16 publications

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“…Interestingly, the co-occurrence of NPM1 and FLT3 mutations is consolidated [112], with a frequency near to twice that of correlation with the wild-type form, suggesting a direct molecular link between them, which has not yet been investigated. This combination is associated with an intermediate prognosis [116]. Moreover, DNMT3A, IDH1, IDH2 and TET2 mutations are identified as concomitant to NPM1 mutations [12,117], confirming the dynamic interplay among AML tumor suppressors.…”

Section: Npm1 Mutationsmentioning

confidence: 75%

Landscape of Tumor Suppressor Mutations in Acute Myeloid Leukemia

Panuzzo

Signorino

Calabrese

et al. 2020

JCM

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Acute myeloid leukemia is mainly characterized by a complex and dynamic genomic instability. Next-generation sequencing has significantly improved the ability of diagnostic research to molecularly characterize and stratify patients. This detailed outcome allowed the discovery of new therapeutic targets and predictive biomarkers, which led to develop novel compounds (e.g., IDH 1 and 2 inhibitors), nowadays commonly used for the treatment of adult relapsed or refractory AML. In this review we summarize the most relevant mutations affecting tumor suppressor genes that contribute to the onset and progression of AML pathology. Epigenetic modifications (TET2, IDH1 and IDH2, DNMT3A, ASXL1, WT1, EZH2), DNA repair dysregulation (TP53, NPM1), cell cycle inhibition and deficiency in differentiation (NPM1, CEBPA, TP53 and GATA2) as a consequence of somatic mutations come out as key elements in acute myeloid leukemia and may contribute to relapse and resistance to therapies. Moreover, spliceosomal machinery mutations identified in the last years, even if in a small cohort of acute myeloid leukemia patients, suggested a new opportunity to exploit therapeutically. Targeting these cellular markers will be the main challenge in the near future in an attempt to eradicate leukemia stem cells.

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Section: Npm1 Mutationsmentioning

confidence: 75%

Landscape of Tumor Suppressor Mutations in Acute Myeloid Leukemia

Panuzzo

Signorino

Calabrese

et al. 2020

JCM

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“…Allogeneic stem cell transplantation in first complete remission (CR1) was associated with a reduced relapse risk in all molecular subgroups with the exception of NPM1mut AML with absent or low ratio FLT3-ITD [27]. Another study showed patients with co-mutated NPM1 and FLT3-TKD may have an exceptionally favorable prognosis [28]. ELN-2017 guidelines recommend upfront testing for FLT3 and measurement of allele ratio (AR) for the prognosis risk stratification.…”

Section: Flt3mentioning

confidence: 99%

Clinical implications of recurrent gene mutations in acute myeloid leukemia

Zhang

et al. 2020

Exp Hematol Oncol

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Acute myeloid leukemia (AML) is a genetically heterogeneous clonal malignancy characterized by recurrent gene mutations. Genomic heterogeneity, patients' individual variability, and recurrent gene mutations are the major obstacles among many factors that impact treatment efficacy of the AML patients. With the application of cost-and time-effective next-generation sequencing (NGS) technologies, an enormous diversity of genetic mutations has been identified. The recurrent gene mutations and their important roles in acute myeloid leukemia (AML) pathogenesis have been studied extensively. In this review, we summarize the recent development on the gene mutation in patients with AML.

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“…Furthermore, FLT3-TKD 1 NPM1c 1 AML patient blasts showed a reduction in FLT3 surface levels as well as increased ER localization of FLT3 compared with FLT3-TKD 1 NPM1 wt blasts ( Figure 2K; supplemental Figure 7B-C). Interestingly, recent human studies suggest that presence of NPM1c significantly changes the prognosis of FLT3-TKD-positive patients, 18 thereby emphasizing the need for elucidating mechanistic links between FLT3-TKD and NPM1c in molecular and murine model studies.…”

Section: Presence Of Npm1c Shifts Flt3-d835y Localization To the Endomentioning

confidence: 99%

NPM1c alters FLT3-D835Y localization and signaling in acute myeloid leukemia

Rudorf

Müller

Klingeberg

et al. 2019

Blood

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Activating mutations in FMS-like tyrosine kinase receptor-3 (FLT3) and Nucleophosmin-1 (NPM1) are most frequent alterations in acute myeloid leukemia (AML), and are often coincidental. The mutational status of NPM1 has strong prognostic relevance to patients with point mutations of the FLT3 tyrosine kinase domain (TKD), but the biological mechanism underlying this effect remains unclear. In the present study, we investigated the effect of the coincidence of NPM1c and FLT3-TKD. Although expression of FLT3-TKD is not sufficient to induce a disease in mice, coexpression with NPM1c rapidly leads to an aggressive myeloproliferative disease in mice with a latency of 31.5 days. Mechanistically, we could show that FLT3-TKD is able to activate the downstream effector molecule signal transducer and activator of transcription 5 (STAT5) exclusively in the presence of mutated NPM1c. Moreover, NPM1c alters the cellular localization of FLT3-TKD from the cell surface to the endoplasmic reticulum, which might thereby lead to the aberrant STAT5 activation. Importantly, aberrant STAT5 activation occurs not only in primary murine cells but also in patients with AML with combined FLT3-TKD and NPM1c mutations. Thus, our data indicate a new mechanism, how NPM1c mislocalizes FLT3-TKD and changes its signal transduction ability.

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Co-occurrence of FLT3-TKD and NPM1 mutations defines a highly favorable prognostic AML group

Cited by 58 publications

References 16 publications

Landscape of Tumor Suppressor Mutations in Acute Myeloid Leukemia

Landscape of Tumor Suppressor Mutations in Acute Myeloid Leukemia

Clinical implications of recurrent gene mutations in acute myeloid leukemia

NPM1c alters FLT3-D835Y localization and signaling in acute myeloid leukemia

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