Targeting IGF2BP3 enhances antileukemic effects of menin-MLL inhibition in MLL-AF4 leukemia
© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved..
ABSTRACT: RNA-binding proteins (RBPs) are emerging as a novel class of therapeutic targets in cancer, including in leukemia, given their important role in posttranscriptional gene regulation, and have the unexplored potential to be combined with existing therapies. The RBP insulin-like growth factor 2 messenger RNA-binding protein 3 (IGF2BP3) has been found to be a critical regulator of MLL-AF4 leukemogenesis and represents a promising therapeutic target. Here, we study the combined effects of targeting IGF2BP3 and menin-MLL interaction in MLL-AF4-driven leukemia in vitro and in vivo, using genetic inhibition with CRISPR-Cas9-mediated deletion of Igf2bp3 and pharmacologic inhibition of the menin-MLL interaction with multiple commercially available inhibitors. Depletion of Igf2bp3 sensitized MLL-AF4 leukemia to the effects of menin-MLL inhibition on cell growth and leukemic initiating cells in vitro. Mechanistically, we found that both Igf2bp3 depletion and menin-MLL inhibition led to increased differentiation in vitro and in vivo, seen in functional readouts and by gene expression analyses. IGF2BP3 knockdown had a greater effect on increasing survival and attenuating disease than pharmacologic menin-MLL inhibition with small molecule MI-503 alone and showed enhanced antileukemic effects in combination. Our work shows that IGF2BP3 is an oncogenic amplifier of MLL-AF4-mediated leukemogenesis and a potent therapeutic target, providing a paradigm for targeting leukemia at both the transcriptional and posttranscriptional level.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:8 |
|---|---|
| Enthalten in: |
Blood advances - 8(2024), 2 vom: 23. Jan., Seite 261-275 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Lin, Tasha L [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 11.01.2024 Date Revised 10.02.2024 published: Print Citation Status MEDLINE |
|---|
| doi: |
10.1182/bloodadvances.2023011132 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM365393576 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM365393576 | ||
| 003 | DE-627 | ||
| 005 | 20240210232936.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1182/bloodadvances.2023011132 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1287.xml |
| 035 | |a (DE-627)NLM365393576 | ||
| 035 | |a (NLM)38048400 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Lin, Tasha L |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Targeting IGF2BP3 enhances antileukemic effects of menin-MLL inhibition in MLL-AF4 leukemia |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 11.01.2024 | ||
| 500 | |a Date Revised 10.02.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. | ||
| 520 | |a ABSTRACT: RNA-binding proteins (RBPs) are emerging as a novel class of therapeutic targets in cancer, including in leukemia, given their important role in posttranscriptional gene regulation, and have the unexplored potential to be combined with existing therapies. The RBP insulin-like growth factor 2 messenger RNA-binding protein 3 (IGF2BP3) has been found to be a critical regulator of MLL-AF4 leukemogenesis and represents a promising therapeutic target. Here, we study the combined effects of targeting IGF2BP3 and menin-MLL interaction in MLL-AF4-driven leukemia in vitro and in vivo, using genetic inhibition with CRISPR-Cas9-mediated deletion of Igf2bp3 and pharmacologic inhibition of the menin-MLL interaction with multiple commercially available inhibitors. Depletion of Igf2bp3 sensitized MLL-AF4 leukemia to the effects of menin-MLL inhibition on cell growth and leukemic initiating cells in vitro. Mechanistically, we found that both Igf2bp3 depletion and menin-MLL inhibition led to increased differentiation in vitro and in vivo, seen in functional readouts and by gene expression analyses. IGF2BP3 knockdown had a greater effect on increasing survival and attenuating disease than pharmacologic menin-MLL inhibition with small molecule MI-503 alone and showed enhanced antileukemic effects in combination. Our work shows that IGF2BP3 is an oncogenic amplifier of MLL-AF4-mediated leukemogenesis and a potent therapeutic target, providing a paradigm for targeting leukemia at both the transcriptional and posttranscriptional level | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 7 | |a Myeloid-Lymphoid Leukemia Protein |2 NLM | |
| 650 | 7 | |a 149025-06-9 |2 NLM | |
| 650 | 7 | |a Transcription Factors |2 NLM | |
| 650 | 7 | |a MLL-AF4 fusion protein, human |2 NLM | |
| 650 | 7 | |a Oncogene Proteins, Fusion |2 NLM | |
| 700 | 1 | |a Jaiswal, Amit K |e verfasserin |4 aut | |
| 700 | 1 | |a Ritter, Alexander J |e verfasserin |4 aut | |
| 700 | 1 | |a Reppas, Jenna |e verfasserin |4 aut | |
| 700 | 1 | |a Tran, Tiffany M |e verfasserin |4 aut | |
| 700 | 1 | |a Neeb, Zachary T |e verfasserin |4 aut | |
| 700 | 1 | |a Katzman, Sol |e verfasserin |4 aut | |
| 700 | 1 | |a Thaxton, Michelle L |e verfasserin |4 aut | |
| 700 | 1 | |a Cohen, Amanda |e verfasserin |4 aut | |
| 700 | 1 | |a Sanford, Jeremy R |e verfasserin |4 aut | |
| 700 | 1 | |a Rao, Dinesh S |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Blood advances |d 2016 |g 8(2024), 2 vom: 23. Jan., Seite 261-275 |w (DE-627)NLM268683263 |x 2473-9537 |7 nnns |
| 773 | 1 | 8 | |g volume:8 |g year:2024 |g number:2 |g day:23 |g month:01 |g pages:261-275 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1182/bloodadvances.2023011132 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 8 |j 2024 |e 2 |b 23 |c 01 |h 261-275 | ||