Evidence map›Paper›PMID 31855575›Full record

ArticleThe Journal of clinical investigation2020

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

Szymon Klossowski, Hongzhi Miao, Katarzyna Kempinska, Tao Wu, Trupta Purohit, EunGi Kim, Brian M Linhares, Dong Chen, Gloria Jih, Eric Perkey and 25 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The Journal of clinical investigation, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 154 papers.

0numbers the graph read from it
0cells of the map it votes in
154citing papers in PubMed
14.9field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

154 citing papers in PubMed, 142 citations in OpenAlex.

  1. Two Decades ofCancers · 2026
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94 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

35 authors at 4 institutions in 1 country.

Szymon KlossowskiDepartment of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
Hongzhi MiaoDepartment of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
Katarzyna KempinskaDepartment of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
Tao WuWellspring Biosciences, Inc., San Diego, California, USA.
Trupta PurohitDepartment of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
EunGi KimDepartment of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
Brian M LinharesDepartment of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
Dong ChenDepartment of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
Gloria JihLife Sciences Institute and.
Eric PerkeyLife Sciences Institute and.
Huang HuangDepartment of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
Miao HeCollege of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA.
Bo WenCollege of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA.
Yi WangWellspring Biosciences, Inc., San Diego, California, USA.
Ke YuWellspring Biosciences, Inc., San Diego, California, USA.
Stanley Chun-Wei LeeMemorial Sloan Kettering Cancer Center, New York, New York, USA.
Gwenn Danet-DesnoyersDivision of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Winifred TrotmanDivision of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Malathi KandarpaDivision of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Anitria CottonSaint Jude Children's Hospital, Memphis, Tennessee, USA.
Omar Abdel-WahabMemorial Sloan Kettering Cancer Center, New York, New York, USA.
Hongwei LeiDepartment of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
Yali DouDepartment of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
Monica GuzmanWeill Cornell Medicine, New York, New York, USA.
Luke PetersonDivision of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Tanja GruberSaint Jude Children's Hospital, Memphis, Tennessee, USA.
Sarah ChoiDepartment of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
Duxin SunCollege of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA.
Pingda RenWellspring Biosciences, Inc., San Diego, California, USA.
Lian-Sheng LiWellspring Biosciences, Inc., San Diego, California, USA.
Yi LiuWellspring Biosciences, Inc., San Diego, California, USA.
Francis BurrowsKura Oncology, Inc., San Diego, California, USA.
Ivan MaillardLife Sciences Institute and.
Tomasz CierpickiDepartment of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
Jolanta GrembeckaDepartment of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
University of Michigan–Ann Arbor · USUniversity of Pennsylvania · USMemorial Sloan Kettering Cancer Center · USWeill Cornell Medicine · US

Funding

X-RAY CRYSTALLOGRAPHYP30CA008748 · NCI · SLOAN-KETTERING INSTITUTE FOR CANCER RES · PI Hongbiao Carl Lekaye · 1985 to 2026
$347.4M
XenograftP30CA046592 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Alexey I Nesvizhskii · 1988 to 2026
$178.2M
MICHIGAN MEDICAL SCIENTIST TRAINING PROGRAMT32GM007863 · NIGMS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI COLLINS, KATHLEEN L. · 1985 to 2024
$38.3M
Development of novel anti-leukemia agents targeting the menin-MLL interactionR01CA160467 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI GREMBECKA, JOLANTA · 2011 to 2021
$3.4M
Development of ASH1L inhibitors for acute leukemiaR01CA244254 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI GREMBECKA, JOLANTA · 2020 to 2024
$2.8M
Selection of Novel Therapies to Ablate Chemoresistant Myeloid Leukemia Stem CellDP2OD007399 · OD · WEILL MEDICAL COLL OF CORNELL UNIV · PI GUZMAN, MONICA L · 2010 to 2010
$2.5M
Molecular functions of the shelterin component ACD/TPP1 in somatic stem cells and tissue homeostasisR01AG050509 · NIA · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI KEEGAN, CATHERINE ELIZABETH, MAILLARD, IVAN · 2015 to 2019
$2.3M
Development of small molecules targeting Ring1B-Bmi1 E3 ligase in leukemiaR01CA207272 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI CIERPICKI, TOMASZ · 2016 to 2020
$2.0M
Targeting protein-protein interactions of Bmi1 oncoproteinR01CA201204 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI GREMBECKA, JOLANTA · 2016 to 2018
$959k
NCI NIH HHS P30 CA008748NCI NIH HHS P30 CA046592NCI NIH HHS R01 CA160467NCI NIH HHS R01 CA201204NCI NIH HHS R01 CA207272NCI NIH HHS R01 CA244254NIA NIH HHS R01 AG050509NIGMS NIH HHS T32 GM007863NIH HHS DP2 OD007399
6 · The paper itself

Abstract

The protein-protein interaction between menin and mixed lineage leukemia 1 (MLL1) plays a critical role in acute leukemias with translocations of the MLL1 gene or with mutations in the nucleophosmin 1 (NPM1) gene. As a step toward clinical translation of menin-MLL1 inhibitors, we report development of MI-3454, a highly potent and orally bioavailable inhibitor of the menin-MLL1 interaction. MI-3454 profoundly inhibited proliferation and induced differentiation in acute leukemia cells and primary patient samples with MLL1 translocations or NPM1 mutations. When applied as a single agent, MI-3454 induced complete remission or regression of leukemia in mouse models of MLL1-rearranged or NPM1-mutated leukemia, including patient-derived xenograft models, through downregulation of key genes involved in leukemogenesis. We also identified MEIS1 as a potential pharmacodynamic biomarker of treatment response with MI-3454 in leukemia, and demonstrated that this compound is well tolerated and did not impair normal hematopoiesis in mice. Overall, this study demonstrates, for the first time to our knowledge, profound activity of the menin-MLL1 inhibitor as a single agent in clinically relevant PDX models of leukemia. These data provide a strong rationale for clinical translation of MI-3454 or its analogs for leukemia patients with MLL1 rearrangements or NPM1 mutations.

Indexed as

Histone-Lysine N-MethyltransferaseLeukemiaMutationMyeloid-Lymphoid Leukemia ProteinNeoplasms, ExperimentalNuclear ProteinsProto-Oncogene ProteinsAntineoplastic AgentsHumansK562 CellsMyeloid Ecotropic Viral Integration Site 1 ProteinNucleophosminRemission InductionU937 CellsAntineoplastic AgentsHistone-Lysine N-MethyltransferaseKMT2A protein, humanMEIS1 protein, humanMEN1 protein, humanMyeloid Ecotropic Viral Integration Site 1 ProteinMyeloid-Lymphoid Leukemia ProteinNPM1 protein, humanNpm1 protein, mouseNuclear ProteinsNucleophosminProto-Oncogene ProteinsDrug therapyHematologyLeukemiasTherapeutics

Identifiers

PMID31855575
PMCPMC6994154
OpenAlexW2995876504

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.