The AML microenvironment catalyzes a stepwise evolution to gilteritinib resistance

Joshi, Sunil; Nechiporuk, Tamilla; Bottomly, Daniel; Piehowski, Paul; Reisz, Julie A.; Pittsenbarger, Janét; Kaempf, Andy; Gosline, Sara J.C.; Wang, Yiting; Hansen, Joshua; Gritsenko, Marina; Hutchinson, Chelsea; Weitz, Karl K.; Moon, Jamie; Cendali, Francesca; Fillmore, Thomas; Tsai, Chia‐Feng; Schepmoes, Athena; Shi, Tujin; Arshad, Osama A.; McDermott, Jason; Babur, Özgün; Watanabe-Smith, Kevin; Demir, Emek; D’Alessandro, Angelo; Liu, Tao; Tognon, Cristina E.; Tyner, Jeffrey W.; McWeeney, Shannon K.; Rodland, Karin D.; Druker, Brian J.; Traer, Elie

doi:10.1016/j.ccell.2021.06.003

Cited by 82 publications

(83 citation statements)

References 108 publications

(144 reference statements)

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“…However, resistance to FLT3i commonly appears, involving paracrine signaling and metabolic sensing from bone marrow microenvironment [12][13][14][15][16][17] , emergence of drug-resistant secondary FLT3 mutations or clonal escape through activation of alternative pathways, as seen with RASactivating mutations [17][18][19][20] .…”

Section: Introductionmentioning

confidence: 99%

C/EBPα confers dependence to fatty acid anabolic pathways and vulnerability to lipid oxidative stress in FLT3-mutant leukemia

Sabatier

Birsen

Tamburini

et al. 2022

Preprint

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While transcription factor C/AAT-enhancer binding protein α (C/EBPα) is critical for normal and leukemic differentiation, its role on cell and metabolic homeostasis is largely unknown in cancer. Here, multi-omics analyses uncovered a coordinated activation of C/EBPα and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism in vivo and in patients with FLT3-mutant acute myeloid leukemia (AML). Mechanistically, C/EBPα regulated FASN-SCD axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPα inactivation decreased mono-unsaturated FAs incorporation to membrane phospholipids through SCD downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress. Moreover, this C/EBPα-dependent adaptation of FA homeostasis was exploited by combining FLT3 and glutathione peroxidase 4 (GPX4) inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of FLT3-mutant AML cells. Altogether, our study reveals a C/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of FLT3-mutant AML with promising therapeutic application

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Section: Introductionmentioning

confidence: 99%

C/EBPα confers dependence to fatty acid anabolic pathways and vulnerability to lipid oxidative stress in FLT3-mutant leukemia

Sabatier

Birsen

Tamburini

et al. 2022

Preprint

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“…The dynamics of leukemic progression, resistance to treatments and relapse have been mostly described in terms of genetic and epigenetic events, as associated to diverse synergistic combinations of mutations (2,(32)(33)(34); however, it is increasingly appreciated that genetic/epigenetic alterations do not entirely explain the complexity and heterogeneity of MN (35)(36)(37), as also inferred from the limited success of drugs targeting single genomic variants [e.g., FLT3 (38,39) or IDH inhibitors (40,41)] or epigenetic traits [e.g., hypomethylating agents, HMA (42,43)]. Indeed, as featured above, there is increasing evidence of multiple mechanisms of immune-evasion during MN development; as a clinical correlate, the immunological eradication of therapy-resistant leukemia stem cells (LSC) by allogeneic hematopoietic stem cell transplant (alloHSCT) is the only strategy to overcome chemoresistance and obtain sustained remission (29,44,45).…”

Section: Current State-of-the-art In Myeloid Neoplasms and Open Chall...mentioning

confidence: 99%

Single-Cell Technologies to Decipher the Immune Microenvironment in Myeloid Neoplasms: Perspectives and Opportunities

et al. 2022

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Myeloid neoplasms (MN) are heterogeneous clonal disorders arising from the expansion of hematopoietic stem and progenitor cells. In parallel with genetic and epigenetic dynamics, the immune system plays a critical role in modulating tumorigenesis, evolution and therapeutic resistance at the various stages of disease progression. Single-cell technologies represent powerful tools to assess the cellular composition of the complex tumor ecosystem and its immune environment, to dissect interactions between neoplastic and non-neoplastic components, and to decipher their functional heterogeneity and plasticity. In addition, recent progress in multi-omics approaches provide an unprecedented opportunity to study multiple molecular layers (DNA, RNA, proteins) at the level of single-cell or single cellular clones during disease evolution or in response to therapy. Applying single-cell technologies to MN holds the promise to uncover novel cell subsets or phenotypic states and highlight the connections between clonal evolution and immune escape, which is crucial to fully understand disease progression and therapeutic resistance. This review provides a perspective on the various opportunities and challenges in the field, focusing on key questions in MN research and discussing their translational value, particularly for the development of more efficient immunotherapies.

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“…In our hands, it induces a strong and deeper response both in vitro and in vivo and is well tolerated in xenografted mice after 4 weeks of treatment. Recently, results from Joshi et al show different early and late resistance mechanisms to gilteritinib [42]. Identification of aurora kinase involvement will allow us to reach CR in resistant patients and then to target FLT3-ITD LIC by the combination of Vps34 inhibitors and mobilizing agents.…”

Section: Discussionmentioning

confidence: 99%

Autophagy Targeting and Hematological Mobilization in FLT3-ITD Acute Myeloid Leukemia Decrease Repopulating Capacity and Relapse by Inducing Apoptosis of Committed Leukemic Cells

Dupont

Huart

Lauvinerie

et al. 2022

Cancers

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Targeting FLT3-ITD in AML using TKI against FLT3 cannot prevent relapse even in the presence of complete remission, suggesting the resistance and/or the persistence of leukemic-initiating cells in the hematopoietic niche. By mimicking the hematopoietic niche condition with cultures at low oxygen concentrations, we demonstrate in vitro that FLT3-ITD AML cells decrease their repopulating capacity when Vps34 is inhibited. Ex vivo, AML FLT3-ITD blasts treated with Vps34 inhibitors recovered proliferation more slowly due to an increase an apoptosis. In vivo, mice engrafted with FLT3-ITD AML MV4-11 cells have the invasion of the bone marrow and blood in 2 weeks. After 4 weeks of FLT3 TKI treatment with gilteritinib, the leukemic burden had strongly decreased and deep remission was observed. When treatment was discontinued, mice relapsed rapidly. In contrast, Vps34 inhibition strongly decreased the relapse rate, and even more so in association with mobilization by G-CSF and AMD3100. These results demonstrate that remission offers the therapeutic window for a regimen using Vps34 inhibition combined with mobilization to target persistent leukemic stem cells and thus decrease the relapse rate.

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The AML microenvironment catalyzes a stepwise evolution to gilteritinib resistance

Cited by 82 publications

References 108 publications

C/EBPα confers dependence to fatty acid anabolic pathways and vulnerability to lipid oxidative stress in FLT3-mutant leukemia

C/EBPα confers dependence to fatty acid anabolic pathways and vulnerability to lipid oxidative stress in FLT3-mutant leukemia

Single-Cell Technologies to Decipher the Immune Microenvironment in Myeloid Neoplasms: Perspectives and Opportunities

Autophagy Targeting and Hematological Mobilization in FLT3-ITD Acute Myeloid Leukemia Decrease Repopulating Capacity and Relapse by Inducing Apoptosis of Committed Leukemic Cells

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