Targeting MEF2D-fusion Oncogenic Transcriptional Circuitries in B-cell Precursor Acute Lymphoblastic Leukemia

Tsuzuki, Shinobu; Yasuda, Takahiko; Kojima, Shinya; Kawazu, Masahito; Akahane, Koshi; Inukai, Takeshi; Imaizumi, Masue; Morishita, Takanobu; Miyamura, Koichi; Ueno, Toshihide; Karnan, Sivasundaram; Ota, Akinobu; Hyodo, Toshinori; Konishi, Hiroyuki; Sanada, Masashi; Nagai, Hirokazu; Horibe, Keizo; Tomita, Akihiro; Suzuki, Kyogo; Muramatsu, Hideki; Takahashi, Yoshiyuki; Miyazaki, Yasushi; Matsumura, Itaru; Kiyoi, Hitoshi; Hosokawa, Yoshitaka; Mano, Hiroyuki; Hayakawa, Fumihiko

doi:10.1158/2643-3230.bcd-19-0080

Cited by 16 publications

(17 citation statements)

References 51 publications

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“…IRF8 is a TF known to regulate normal myeloid and B cell development (Holtschke et al, 1996;Lu et al, 2003;Tamura et al, 2000;Wang et al, 2008). Recently, MEF2D translocations have been shown to regulate essential precursor B cell receptor signaling in B cell acute lymphoblastic leukemia (Tsuzuki et al, 2020). In AML, we show that IRF8 and MEF2D mutually support transcription, forming a positive-feedback regulatory loop to sustain the oncogenic cell state (Figure 7O).…”

Section: Discussionmentioning

confidence: 67%

ZMYND8-regulated IRF8 transcription axis is an acute myeloid leukemia dependency

et al. 2021

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Section: Discussionmentioning

confidence: 67%

ZMYND8-regulated IRF8 transcription axis is an acute myeloid leukemia dependency

et al. 2021

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“…The rearrangements result in enhanced MEF2D transcriptional activity, increased HDAC9 expression and sensitivity to histone deacetylase inhibitors, such as panobinostat [85]. MEF2D has also been implicated in a core transcription factor regulatory circuit involving SREBF1 that regulates pre-BCR and lipid metabolism, that are therapeutic vulnerabilities [89]. Sensitivity to staurosporine and venetoclax has been also described [90].…”

Section: Dux4 Mef2d Znf384 and Nutm1 Gene Fusionsmentioning

confidence: 99%

Biologic and Therapeutic Implications of Genomic Alterations in Acute Lymphoblastic Leukemia

Iacobucci

Kimura

Mullighan

2021

JCM

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Acute lymphoblastic leukemia (ALL) is the most successful paradigm of how risk-adapted therapy and detailed understanding of the genetic alterations driving leukemogenesis and therapeutic response may dramatically improve treatment outcomes, with cure rates now exceeding 90% in children. However, ALL still represents a leading cause of cancer-related death in the young, and the outcome for older adolescents and young adults with ALL remains poor. In the past decade, next generation sequencing has enabled critical advances in our understanding of leukemogenesis. These include the identification of risk-associated ALL subtypes (e.g., those with rearrangements of MEF2D, DUX4, NUTM1, ZNF384 and BCL11B; the PAX5 P80R and IKZF1 N159Y mutations; and genomic phenocopies such as Ph-like ALL) and the genomic basis of disease evolution. These advances have been complemented by the development of novel therapeutic approaches, including those that are of mutation-specific, such as tyrosine kinase inhibitors, and those that are mutation-agnostic, including antibody and cellular immunotherapies, and protein degradation strategies such as proteolysis-targeting chimeras. Herein, we review the genetic taxonomy of ALL with a focus on clinical implications and the implementation of genomic diagnostic approaches.

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“…Through continuous efforts to explore, Mylotarg was approved again for treatment of new indications extended to relapsed or refractory (R/R) CD33-positive AML in pediatric and older patients in 2017 [ 33 ]. On the other hand, CD20 is a B cell differentiation antigen located only in pre-B cells and mature B cells which can act as the diagnostic target in CLL and ALL [ 34 , 35 , 36 , 37 , 38 ]. Based on this target, MRG001, another ADC drug composed of chimeric anti-CD20 mAbs with anti-microtubulin agent monomethyl auristatin E (MMAE), is currently being evaluated in a phase I study in patients with CD20-positive relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) [ 39 ].…”

Section: CD Markers Are Great Therapeutic Targets For Hematologic Mal...mentioning

confidence: 99%

The Landscape of Nucleic-Acid-Based Aptamers for Treatment of Hematologic Malignancies: Challenges and Future Directions

et al. 2022

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Hematologic malignancies, including leukemia, lymphoma, myeloproliferative disorder and plasma cell neoplasia, are genetically heterogeneous and characterized by an uncontrolled proliferation of their corresponding cell lineages in the bone marrow, peripheral blood, tissues or plasma. Although there are many types of therapeutic drugs (e.g., TKIs, chemotherapy drugs) available for treatment of different malignancies, the relapse, drug resistance and severe side effects due to the lack of selectivity seriously limit their clinical application. Currently, although antibody–drug conjugates have been well established as able to target and deliver highly potent chemotherapy agents into cancer cells for the reduction of damage to healthy cells and have achieved success in leukemia treatment, they still also have shortcomings such as high cost, high immunogenicity and low stability. Aptamers are ssDNA or RNA oligonucleotides that can also precisely deliver therapeutic agents into cancer cells through specifically recognizing the membrane protein on cancer cells, which is similar to the capabilities of monoclonal antibodies. Aptamers exhibit higher binding affinity, lower immunogenicity and higher thermal stability than antibodies. Therefore, in this review we comprehensively describe recent advances in the development of aptamer–drug conjugates (ApDCs) with cytotoxic payload through chemical linkers or direct incorporation, as well as further introduce the latest promising aptamers-based therapeutic strategies such as aptamer–T cell therapy and aptamer–PROTAC, clarifying their bright application, development direction and challenges in the treatment of hematologic malignancies.

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Targeting MEF2D-fusion Oncogenic Transcriptional Circuitries in B-cell Precursor Acute Lymphoblastic Leukemia

Cited by 16 publications

References 51 publications

ZMYND8-regulated IRF8 transcription axis is an acute myeloid leukemia dependency

ZMYND8-regulated IRF8 transcription axis is an acute myeloid leukemia dependency

Biologic and Therapeutic Implications of Genomic Alterations in Acute Lymphoblastic Leukemia

The Landscape of Nucleic-Acid-Based Aptamers for Treatment of Hematologic Malignancies: Challenges and Future Directions

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