Synergistic targeting of <i>FLT3</i> mutations in AML via combined menin-MLL and FLT3 inhibition

Dzama, Margarita M.; Steiner, Marlene; Rausch, Johanna; Sasca, Daniel; Schönfeld, Jonas; Kunz, Kerstin; Taubert, Martha C.; McGeehan, Gerard M.; Chen, Chun-Wei; Mupo, Annalisa; Hähnel, Patricia S.; Theobald, Matthias; Kindler, Thomas; Koche, Richard P.; Vassiliou, George S.; Armstrong, Scott A.; Kühn, Michael W.M.

doi:10.1182/blood.2020005037

Cited by 75 publications

(81 citation statements)

References 66 publications

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“…In some subsets of AML, molecular diagnostics can suggest the therapies most likely to give a favorable outcome such as expression of cell surface marker CD33 or mutations in specific genes such as FLT3/IDH1/IDH2 (8,11,12). Among the most frequent mutations in AML are those affecting nucleophosmin 1 (NPM1) which is possible to target experimentally, as recently demonstrated (13)(14)(15)(16). Similarly, mutations in TP53 are associated with chemo-resistance and therapies aimed at restoring P53 function are in development (17).…”

Section: Introductionmentioning

confidence: 99%

Colony Stimulating Factor 1 Receptor in Acute Myeloid Leukemia

2021

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Acute myeloid leukemia (AML) is an aggressive heterogeneous blood cancer derived from hematopoietic stem cells. Tumor-stromal interactions in AML are of importance for disease development and therapy resistance, and bone marrow stroma seem like an attractive therapeutic target. Of particular interest is colony stimulating factor 1 receptor (CSF1R, M-CSFR, c-FMS, CD115) and its role in regulating plasticity of tumor-associated macrophages. We discuss first the potential of CSF1R-targeted therapy as an attractive concept with regards to the tumor microenvironment in the bone marrow niche. A second therapy approach, supported by preclinical research, also suggests that CSF1R-targeted therapy may increase the beneficial effect of conventional and novel therapeutics. Experimental evidence positioning inhibitors of CSF1R as treatment should, together with data from preclinical and early phase clinical trials, facilitate translation and clinical development of CSF1R-targeted therapy for AML.

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Section: Introductionmentioning

confidence: 99%

Colony Stimulating Factor 1 Receptor in Acute Myeloid Leukemia

2021

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“…[51][52][53] Understanding the basis of the molecular synergy between FLT3 and class-defining mutations can help develop rational combination therapies, as was shown recently with mutant NPM1. 54 However, a significant proportion (;20%) of FLT3-ITD AMLs do not harbor class-defining mutations or, in many cases, any known oncogenic mutations. 4 Although it is possible that as yet undiscovered somatic mutations are present in these cases, the large number of AML exomes and genomes studied so far make this unlikely.…”

Section: Discussionmentioning

confidence: 99%

SETBP1 overexpression acts in the place of class-defining mutations to drive FLT3-ITD–mutant AML

et al. 2021

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Advances in cancer genomics have revealed genomic classes of acute myeloid leukemia (AML) characterized by class-defining mutations, such as chimeric fusion genes or in genes such as NPM1, MLL, and CEBPA. These class-defining mutations frequently synergize with internal tandem duplications in FLT3 (FLT3-ITDs) to drive leukemogenesis. However, ∼20% of FLT3-ITD–positive AMLs bare no class-defining mutations, and mechanisms of leukemic transformation in these cases are unknown. To identify pathways that drive FLT3-ITD mutant AML in the absence of class-defining mutations, we performed an insertional mutagenesis (IM) screening in Flt3-ITD mice, using Sleeping Beauty transposons. All mice developed acute leukemia (predominantly AML) after a median of 73 days. Analysis of transposon insertions in 38 samples from Flt3-ITD/IM leukemic mice identified recurrent integrations at 22 loci, including Setbp1 (20/38), Ets1 (11/38), Ash1l (8/38), Notch1 (8/38), Erg (7/38), and Runx1 (5/38). Insertions at Setbp1 led exclusively to AML and activated a transcriptional program similar, but not identical, to those of NPM1-mutant and MLL-rearranged AMLs. Guide RNA targeting of Setbp1 was highly detrimental to Flt3ITD/+/Setbp1IM+, but not to Flt3ITD/+/Npm1cA/+, AMLs. Also, analysis of RNA-sequencing data from hundreds of human AMLs revealed that SETBP1 expression is significantly higher in FLT3-ITD AMLs lacking class-defining mutations. These findings propose that SETBP1 overexpression collaborates with FLT3-ITD to drive a subtype of human AML. To identify genetic vulnerabilities of these AMLs, we performed genome-wide CRISPR-Cas9 screening in Flt3ITD/+/Setbp1IM+ AMLs and identified potential therapeutic targets, including Kdm1a, Brd3, Ezh2, and Hmgcr. Our study gives new insights into epigenetic pathways that can drive AMLs lacking class-defining mutations and proposes therapeutic approaches against such cases.

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“…For those patients with MLL-r or mutant NPM1 and an additional FLT3 mutation, the combination of a menin inhibitor with an FLT3 inhibitor appears to be promising. 60 …”

Section: Targeted Therapymentioning

confidence: 99%

Treatment for Relapsed/Refractory Acute Myeloid Leukemia

Thol

Heuser

2021

HemaSphere

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Patients with relapsed or refractory (r/r) acute myeloid leukemia (AML) have a poor prognosis and treatment remains challenging. For the majority of r/r patients, allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment approach. Salvage therapy is given in order to reduce the leukemia load prior to transplantation. Patients achieving complete remission prior to allogeneic HSCT have a more favorable outcome. Intensive salvage regimens commonly consist of an anthracycline and high-dose cytarabine backbone. Donor lymphocyte infusions have shown efficacy in patients relapsing after allogeneic HSCT. For patients who cannot be intensively treated (eg, elderly AML patients), outcome is generally very poor and combinations with novel agents are currently under investigation. Mutational analysis should be repeated at the time of relapse to identify aberrations that can be targeted with new agents. For r/r AML patients with mutated fms-related tyrosine kinase 3 (FLT3), gilteritinib has shown superior results to intensive salvage regimens. The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved gilteritinib for FLT3 mutated r/r AML patients. Ivosidenib and enasidenib, inhibitors for mutated isocitrate dehydrogenase (IDH) 1 and 2, respectively, have received approval for IDH1/IDH2 mutated r/r AML by the FDA (not EMA). APR-246 restores the function of mutated TP53 and early study results are promising. Other agents targeting CD47, menin, neural-precursor-cell-expressed developmentally down-regulated 8, as well as bispecific antibodies or chimeric antigen receptor T cells are under investigation. Further trials are needed to understand how to best combine novel agents with each other or with chemotherapy.

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

Cited by 75 publications

References 66 publications

Colony Stimulating Factor 1 Receptor in Acute Myeloid Leukemia

Colony Stimulating Factor 1 Receptor in Acute Myeloid Leukemia

SETBP1 overexpression acts in the place of class-defining mutations to drive FLT3-ITD–mutant AML

Treatment for Relapsed/Refractory Acute Myeloid Leukemia

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