Identification of a germline F692L drug resistance variant in cis with Flt3-internal tandem duplication in knock-in mice

Dovey, Oliver M.; Chen, Bin; Mupo, Annalisa; Friedrich, M.; Grove, Carolyn; Cooper, Jonathan; Lee, Benjamin; Varela, Ignacio; Huang, Yue; Vassiliou, George S.

doi:10.3324/haematol.2016.146159

Cited by 5 publications

(10 citation statements)

References 16 publications

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“…We next assessed FLT3 inhibition in the murine Npm1 CA/1 Flt3 ITD/1 leukemia cells known to harbor the F692L point ("gatekeeper") mutation that mediates resistance to most FLT3 inhibitors. 48 In accordance with published data, the cells showed hardly any response to quizartinib, and the IC 50 values of ponatinib, crenolanib, and gilteritinib, were shifted to higher concentrations compared with the values determined from the MOLM13 and MV411 cells that lacked the F692L mutation. Murine Hoxa9-Meis1-transformed cells without an FLT3 mutation were not affected by FLT3 inhibition (Figure 2C-E; supplemental Figure 3D-F).…”

Section: Resultssupporting

confidence: 89%

Synergistic targeting of FLT3 mutations in AML via combined menin-MLL and FLT3 inhibition

Dzama

Steiner

Rausch

et al. 2020

Blood

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The interaction of Menin (MEN1) and MLL (MLL1, KMT2A) is a dependency and potential therapeutic opportunity against NPM1-mutant (NPM1mut) and MLL-rearranged (MLL-r) leukemias. Concomitant activating driver mutations in the gene encoding the tyrosine kinase FLT3 occur in both leukemias and are particularly common in the NPM1mut subtype. Transcriptional profiling upon pharmacological inhibition of the Menin-MLL complex revealed specific changes in gene expression with downregulation of the MEIS1 transcription-factor and its transcriptional target gene FLT3 being most pronounced. Combining Menin-MLL-inhibition with specific small-molecule kinase inhibitors of FLT3-phosphorylation resulted in a significantly superior reduction of phosphorylated FLT3 and transcriptional suppression of genes downstream to FLT3 signaling. The drug combination induced synergistic inhibition of proliferation as well as enhanced apoptosis and differentiation compared to single-drug treatment in models of human and murine NPM1mut and MLL-r leukemias harboring an FLT3 mutation. Primary AML cells harvested from patients with NPM1mutFLT3mut AML showed significantly better responses to combined Menin and FLT3-inhibition than to single-drug or vehicle control treatment, while AML cells with wildtype NPM1, MLL, and FLT3 were not affected by any of the two drugs. In vivo treatment of leukemic animals with MLL-r FLT3mut leukemia reduced leukemia burden significantly and prolonged survival compared to the single-drug and vehicle control groups. Our data suggest that combined Menin-MLL and FLT3-inhibition represents a novel and promising therapeutic strategy for patients with NPM1mut or MLL-r leukemia and concurrent FLT3 mutation.

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Section: Resultssupporting

confidence: 89%

Synergistic targeting of FLT3 mutations in AML via combined menin-MLL and FLT3 inhibition

Dzama

Steiner

Rausch

et al. 2020

Blood

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“…FLT3-ITD leads to constitutive activation of JAK/STAT signaling, driving growth and transformation of hematopoietic cells. [35][36][37] In keeping with this, our transcriptome analysis revealed that genes involved in JAK/STAT signaling (Stat5a, Cish, Socs2) were differentially expressed in Figure 8B). We confirmed by RNA-seq that this was due to activation of a JAK/STAT program in Npm1 cA/1 ;Nras G12D/1 AML cells (supplemental Figure 9).…”

Section: Hoxa Gene Expression Is Unaltered In Npm1-mutant Early Multimentioning

confidence: 74%

Molecular synergy underlies the co-occurrence patterns and phenotype of NPM1-mutant acute myeloid leukemia

Dovey

Cooper

Mupo

et al. 2017

Blood

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Key Points• Npm1c and Nras-G12D comutation in mice leads to AML with a longer latency and a more mature phenotype than the Npm1c/Flt3-ITD combination.• Mutant Flt3 or Nras allele amplification is the dominant mode of progression in both Npm1c/Flt3-ITD and Npm1c/ Nras-G12D murine AML.NPM1 mutations define the commonest subgroup of acute myeloid leukemia (AML) and frequently co-occur with FLT3 internal tandem duplications (ITD) or, less commonly, NRAS or KRAS mutations. Co-occurrence of mutant NPM1 with FLT3-ITD carries a significantly worse prognosis than NPM1-RAS combinations. To understand the molecular basis of these observations, we compare the effects of the 2 combinations on hematopoiesis and leukemogenesis in knock-in mice. . During AML evolution, both models acquired additional copies of the mutant Flt3 or Nras alleles, but only Npm1 cA/1 ;Nras G12D/1 mice showed acquisition of other human AML mutations, including IDH1 R132Q. We also find, using primary Cas9-expressing AMLs, that Hoxa genes and selected interactors or downstream targets are required for survival of both types of double-mutant AML. Our results show that molecular complementarity underlies the higher frequency and significantly worse prognosis associated with NPM1c/FLT3-ITD vs NPM1/NRAS-G12D-mutant AML and functionally confirm the role of HOXA genes in

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“…Quizartinib preferentially protects WT MPPs from 5-FU cytotoxicity in WT/FLT3-ITD(F692L) chimeric mice FLT3-internal tandem duplication (ITD) mutations are found in about 25% of human acute myeloid leukemias (AMLs), and knock-in mice with an ITD mutation develop a myeloproliferative disease character-ized by an expansion of highly proliferative MPPs (32). These mice carry a germline F692L mutation in FLT3 that confers resistance to quizartinib (33). The origin of this mutation is not known, but it corresponds to F691L mutations found in FLT3-ITD + AML patients who develop resistance to quizartinib (34).…”

Section: Quizartinib Priming Protects Against Gemcitabineinduced Myel...mentioning

confidence: 99%

Preventing chemotherapy-induced myelosuppression by repurposing the FLT3 inhibitor quizartinib

et al. 2017

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We describe an approach to inhibit chemotherapy-induced myelosuppression. We found that short-term exposure of mice to the FLT3 inhibitor quizartinib induced the transient quiescence of multipotent progenitors (MPPs). This property of quizartinib conferred marked protection to MPPs in mice receiving fluorouracil or gemcitabine. The protection resulted in the rapid recovery of bone marrow and blood cellularity, thus preventing otherwise lethal myelosuppression. A treatment strategy involving quizartinib priming that protected wild-type bone marrow progenitors, but not leukemic cells, from fluorouracil provided a more effective treatment than conventional induction therapy in mouse models of acute myeloid leukemia. This strategy has the potential to be extended for use in other cancers where FLT3 inhibition does not adversely affect the effectiveness of chemotherapy. Thus, the addition of quizartinib to cancer treatment regimens could markedly improve cancer patient survival and quality of life.

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Identification of a germline F692L drug resistance variant in cis with Flt3-internal tandem duplication in knock-in mice

Cited by 5 publications

References 16 publications

Synergistic targeting of FLT3 mutations in AML via combined menin-MLL and FLT3 inhibition

Synergistic targeting of FLT3 mutations in AML via combined menin-MLL and FLT3 inhibition

Molecular synergy underlies the co-occurrence patterns and phenotype of NPM1-mutant acute myeloid leukemia

Preventing chemotherapy-induced myelosuppression by repurposing the FLT3 inhibitor quizartinib

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