Menin inhibitor MI-3454 induces remission in MLL1-rearranged and NPM1-mutated models of leukemia

Kłossowski, Szymon; Miao, Hongzhi; Kempińska, Katarzyna; Wu, Tao; Purohit, Trupta; Kim, EunGi; Linhares, Brian M.; Chen, Dong; Jih, Gloria; Perkey, Eric; Huang, Huang; He, Miao; Wen, Bo; Wang, Yi; Yu, Ke; Lee, Stanley Chun-Wei; Danet-Desnoyers, Gwenn; Trotman, Winifred; Kandarpa, Malathi; Cotton, Anitria; Abdel-Wahab, Omar; Lei, Hongwei; Dou, Yali; Guzmán, Mónica L.; Peterson, Luke F.; Grüber, Tanja A.; Choi, Sarah M.; Sun, Duxin; Ren, Pingda; Li, Liansheng; Liu, Yi; Burrows, Francis; Maillard, Ivan; Cierpicki, Tomasz; Grembecka, Jolanta

doi:10.1172/jci129126

Cited by 178 publications

(169 citation statements)

References 44 publications

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“…Interestingly, the expression levels of HOX genes were not affected by this drug despite the dramatic anti-tumor effect, indicating maybe that MEIS1 could be the shared vulnerability for AML with NPM1c . Similarly, Klossowski and colleagues used the menin inhibitor MI-3454 in a mouse model of NPM1 -mutated AML and in patient-derived xenograft models, and showed remarkable anti-leukemic activity, this time, however, downregulating HOX genes and MEIS1 [ 109 ]. Both of these inhibitors have analogs currently under investigation in clinical trials which just started (NCT04065399, NCT04067336).…”

Section: Npm1 and Leukemiamentioning

confidence: 99%

Nucleophosmin 1 Mutations in Acute Myeloid Leukemia

Zarka

Short

Kanagal‐Shamanna

et al. 2020

Genes

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Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein involved in ribosome biogenesis, the maintenance of genomic integrity and the regulation of the ARF-p53 tumor-suppressor pathway among multiple other functions. Mutations in the corresponding gene cause a cytoplasmic dislocation of the NPM1 protein. These mutations are unique to acute myeloid leukemia (AML), a disease characterized by clonal expansion, impaired differentiation and the proliferation of myeloid cells in the bone marrow. Despite our improved understanding of NPM1 mutations and their consequences, the underlying leukemia pathogenesis is still unclear. Recent studies that focused on dysregulated gene expression in AML with mutated NPM1 have shed more light into these mechanisms. In this article, we review the current evidence on normal functions of NPM1 and aberrant functioning in AML, and highlight investigational strategies targeting these mutations.

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Section: Npm1 and Leukemiamentioning

confidence: 99%

Nucleophosmin 1 Mutations in Acute Myeloid Leukemia

Zarka

Short

Kanagal‐Shamanna

et al. 2020

Genes

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“…MENIN-MLL interaction inhibitors (Klossowski et al, 2019;Krivtsov et al, 2019) to treat malignant leukemia with subsets of MLL-and NUP98-fusions.…”

Section: --22mentioning

confidence: 99%

HBO1-MLL interaction promotes AF4/ENL/P-TEFb-mediated leukemogenesis

Takahashi

Kanai

Okuda

et al. 2021

Preprint

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Leukemic oncoproteins cause uncontrolled self-renewal of hematopoietic progenitors by aberrant gene activation, eventually causing leukemia. However, the molecular mechanism of aberrant gene activation remains elusive. Here, we showed that leukemic MLL fusion proteins associate with the HBO1 histone acetyltransferase (HAT) complex through their TRX2 domain. Among many MLL fusions, MLL-ELL particularly depended on its association with the HBO1 complex for leukemic transformation. The C-terminal portion of ELL provided a binding platform for multiple factors including AF4, EAF1 and p53. MLL-ELL activated gene expression by loading an AF4 /ENL/P-TEFb complex (AEP) onto the target promoters. The HBO1 complex promoted the use of AEP over EAF1 and p53. Moreover, the NUP98-HBO1 fusion protein exerted its oncogenic properties via interaction with MLL but not its intrinsic HAT activity. Thus, the interaction between HBO1 and MLL is an important nexus in leukemic transformation, which may serve as a therapeutic target for drug development.

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“…Translocations of the mixed lineage leukemia 1 (MLL1, MLL or KMT2A) gene are found in approximately 5-10% of AML, resulting in unfavorable disease. Fusion with other proteins leads to enhanced proliferation without cell differentiation, thus driving the development of leukemia [103]. In pre-clinical trials, the menin-inhibitor MI-3454 profoundly inhibited cell proliferation while enhancing differentiation in AML patients with either MLL or NPM1 mutations.…”

Section: Drugs In the Pipelinementioning

confidence: 99%

Advances in Acute Myeloid Leukemia: Recently Approved Therapies and Drugs in Development

Stanchina

Soong

Zheng-Lin

et al. 2020

Cancers

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Acute myeloid leukemia (AML) is a genetically heterogeneous malignancy comprised of various cytogenetic and molecular abnormalities that has notoriously been difficult to treat with an overall poor prognosis. For decades, treatment options were limited to either intensive chemotherapy with anthracycline and cytarabine-based regimens (7 + 3) or lower intensity regimens including hypomethylating agents or low dose cytarabine, followed by either allogeneic stem cell transplant or consolidation chemotherapy. Fortunately, with the influx of rapidly evolving molecular technologies and new genetic understanding, the treatment landscape for AML has dramatically changed. Advances in the formulation and delivery of 7 + 3 with liposomal cytarabine and daunorubicin (Vyxeos) have improved overall survival in secondary AML. Increased understanding of the genetic underpinnings of AML has led to targeting actionable mutations such as FLT3, IDH1/2 and TP53, and BCL2 or hedgehog pathways in more frail populations. Antibody drug conjugates have resurfaced in the AML landscape and there have been numerous advances utilizing immunotherapies including immune checkpoint inhibitors, antibody-drug conjugates, bispecific T cell engager antibodies, chimeric antigen receptor (CAR)-T therapy and the development of AML vaccines. While there are dozens of ongoing studies and new drugs in the pipeline, this paper serves as a review of the advances achieved in the treatment of AML in the last several years and the most promising future avenues of advancement

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Menin inhibitor MI-3454 induces remission in MLL1-rearranged and NPM1-mutated models of leukemia

Cited by 178 publications

References 44 publications

Nucleophosmin 1 Mutations in Acute Myeloid Leukemia

Nucleophosmin 1 Mutations in Acute Myeloid Leukemia

HBO1-MLL interaction promotes AF4/ENL/P-TEFb-mediated leukemogenesis

Advances in Acute Myeloid Leukemia: Recently Approved Therapies and Drugs in Development

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