Last update 19 Sep 2024

MLLT1

Last update 19 Sep 2024

Basic Info

Synonyms

ENL, LTG19, MLLT1

+ [4]

Introduction

Chromatin reader component of the super elongation complex (SEC), a complex required to increase the catalytic rate of RNA polymerase II transcription by suppressing transient pausing by the polymerase at multiple sites along the DNA (PubMed:20159561, PubMed:20471948). Specifically recognizes and binds acetylated and crotonylated histones, with a preference for histones that are crotonylated (PubMed:27105114). Has a slightly higher affinity for binding histone H3 crotonylated at 'Lys-27' (H3K27cr) than 'Lys-20' (H3K9cr20) (PubMed:27105114). Acts as a key chromatin reader in acute myeloid leukemia by recognizing and binding to acetylated histones via its YEATS domain, thereby regulating oncogenic gene transcription.

Drugs associated with MLLT1

PFI-6

Target

MLLT1 x MLLT3

Mechanism

MLLT1 modulators [+1]

Active Org.

Pfizer Inc.

Originator Org.

Pfizer Inc.

Active Indication

Diagnostic agents

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

ENL-YEATS inhibitors (Rockefeller University)

Target

MLLT1

Mechanism

MLLT1 inhibitors

Active Org.

The Rockefeller University

Originator Org.

The Rockefeller University

Active Indication

Acute Myeloid Leukemia

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

SR-0813

Target

MLLT1 x MLLT3

Mechanism

MLLT1 inhibitors [+1]

Active Org.

The Scripps Research Institute

Originator Org.

The Scripps Research Institute

Active Indication

acute leukemia

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with MLLT1

100 Translational Medicine associated with MLLT1

0 Patents (Medical) associated with MLLT1

340

Literatures (Medical) associated with MLLT1

30 Aug 2024·Science Advances

A potent and selective ENL degrader suppresses oncogenic gene expression and leukemia progression

Article

Author: Xie, Ling ; Xue, Zhaoyu ; Chen, Xian ; Xuan, Hongwen ; Shi, Xiaobing ; Kaniskan, H Ümit ; Qin, Lihuai ; Xu, Longxia ; Wen, Hong ; Huang, Mengying ; Luo, Kaixiu ; Dale, Brandon ; Su, Yangzhou ; Harsh, Josiah ; Jin, Jian

The histone acylation reader eleven-nineteen leukemia (ENL) plays a pivotal role in sustaining oncogenesis in acute leukemias, particularly in mixed-lineage leukemia –rearranged ( MLL -r) leukemia. ENL relies on its reader domain to recognize histone lysine acylation promoting oncogenic gene expression and leukemia progression. Here, we report the development of MS41, a highly potent and selective von Hippel–Lindau–recruiting ENL degrader that effectively inhibits the growth of ENL-dependent leukemia cells. MS41-induced ENL degradation reduces the chromatin occupancy of ENL-associated transcription elongation machinery, resulting in the suppression of key oncogenic gene expression programs and the activation of differentiation genes. MS41 is well-tolerated in vivo and substantially suppresses leukemia progression in a xenograft mouse model of MLL-r leukemia. Notably, MS41 also induces the degradation of mutant ENL proteins identified in Wilms’ tumors. Our findings emphasize the therapeutic potential of pharmacological ENL degradation for treating ENL-dependent cancers, making MS41 not only a valuable chemical probe but also potential anticancer therapeutic for further development.

02 Aug 2024·Cancer Discovery

Condensate-Promoting ENL Mutation Drives Tumorigenesis In Vivo Through Dynamic Regulation of Histone Modifications and Gene Expression

Article

Author: Tang, Sylvia ; Outen, Riley ; Gong, Chujie ; Mathias, Kaeli M. ; Maillard, Ivan ; Joyce, Eric F. ; Wan, Liling ; Song, Lele ; Vanderbeck, Ashley ; Liu, Yiman ; Nguyen, Son C. ; Wertheim, Gerald B. ; Li, Qinglan ; Budinich, Krista A.

AbstractGain-of-function mutations in the histone acetylation “reader” eleven-nineteen-leukemia (ENL), found in acute myeloid leukemia (AML) and Wilms tumor, are known to drive condensate formation and gene activation in cellular systems. However, their role in tumorigenesis remains unclear. Using a conditional knock-in mouse model, we show that mutant ENL perturbs normal hematopoiesis, induces aberrant expansion of myeloid progenitors, and triggers rapid onset of aggressive AML. Mutant ENL alters developmental and inflammatory gene programs in part by remodeling histone modifications. Mutant ENL forms condensates in hematopoietic stem/progenitor cells at key leukemogenic genes, and disrupting condensate formation via mutagenesis impairs its chromatin and oncogenic function. Moreover, treatment with an acetyl-binding inhibitor of the mutant ENL displaces these condensates from target loci, inhibits mutant ENL-induced chromatin changes, and delays AML initiation and progression in vivo. Our study elucidates the function of ENL mutations in chromatin regulation and tumorigenesis and demonstrates the potential of targeting pathogenic condensates in cancer treatment.Significance: A direct link between ENL mutations, condensate formation, and tumorigenesis is lacking. This study elucidates the function and mechanism of ENL mutations in leukemogenesis, establishing these mutations as bona fide oncogenic drivers. Our results also support the role of condensate dysregulation in cancer and reveal strategies to target pathogenic condensates.

25 Jun 2024·Blood Advances

Optimized cytogenetic risk-group stratification of KMT2A-rearranged pediatric acute myeloid leukemia

Article

Author: Tierens, Anne ; Polychronopoulou, Sophia ; Gamis, Alan ; Leverger, Guy ; Kaspers, Gertjan J L ; Rasche, Mareike ; Hasle, Henrik ; Miyamura, Takako ; Elitzur, Sarah ; Bart-Delabesse, Emmanuelle ; Stary, Jan ; Kelaidi, Charikleia ; Buldini, Barbara ; Rubnitz, Jeffrey E ; Dworzak, Michael N ; Aplenc, Richard ; Jiang, Yilin ; Guest, Erin ; Zwaan, C Michel ; Goemans, Bianca F ; Harrison, Christine J ; van Weelderen, Romy E ; Ha, Shau-Yin ; Fernández Navarro, José M ; Gerbing, Robert B ; Tomizawa, Daisuke ; Klein, Kim ; Norén-Nyström, Ulrika ; Locatelli, Franco ; De Moerloose, Barbara ; Arad-Cohen, Nira ; Lapillonne, Hélène ; de Groot-Kruseman, Hester A ; Abrahamsson, Jonas ; Alonzo, Todd

AbstractA comprehensive international consensus on the cytogenetic risk-group stratification of KMT2A-rearranged (KMT2A-r) pediatric acute myeloid leukemia (AML) is lacking. This retrospective (2005-2016) International Berlin-Frankfurt-Münster Study Group study on 1256 children with KMT2A-r AML aims to validate the prognostic value of established recurring KMT2A fusions and additional cytogenetic aberrations (ACAs) and to define additional, recurring KMT2A fusions and ACAs, evaluating their prognostic relevance. Compared with our previous study, 3 additional, recurring KMT2A-r groups were defined: Xq24/KMT2A::SEPT6, 1p32/KMT2A::EPS15, and 17q12/t(11;17)(q23;q12). Across 13 KMT2A-r groups, 5-year event-free survival probabilities varied significantly (21.8%-76.2%; P < .01). ACAs occurred in 46.8% of 1200 patients with complete karyotypes, correlating with inferior overall survival (56.8% vs 67.9%; P < .01). Multivariable analyses confirmed independent associations of 4q21/KMT2A::AFF1, 6q27/KMT2A::AFDN, 10p12/KMT2A::MLLT10, 10p11.2/KMT2A::ABI1, and 19p13.3/KMT2A::MLLT1 with adverse outcomes, but not those of 1q21/KMT2A::MLLT11 and trisomy 19 with favorable and adverse outcomes, respectively. Newly identified ACAs with independent adverse prognoses were monosomy 10, trisomies 1, 6, 16, and X, add(12p), and del(9q). Among patients with 9p22/KMT2A::MLLT3, the independent association of French-American-British–type M5 with favorable outcomes was confirmed, and those of trisomy 6 and measurable residual disease at end of induction with adverse outcomes were identified. We provide evidence to incorporate 5 adverse-risk KMT2A fusions into the cytogenetic risk-group stratification of KMT2A-r pediatric AML, to revise the favorable-risk classification of 1q21/KMT2A::MLLT11 to intermediate risk, and to refine the risk-stratification of 9p22/KMT2A::MLLT3 AML. Future studies should validate the associations between the newly identified ACAs and outcomes and unravel the underlying biological pathogenesis of KMT2A fusions and ACAs.

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MLLT1

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