# Targeting an RNA Binding Protein Network in Acute Myeloid Leukemia

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2022 · $544,735

## Abstract

RNA-binding proteins (RBPs) are essential modulators of transcription and translation frequently dysregulated
in cancer. We recently systematically interrogated RBP dependencies in a number of human cancers using a
comprehensive CRISPR/Cas9 domain-focused screen targeting RNA-binding domains (RBDs) of 490 classical
RBPs. This uncovered a network of physically interacting RBPs upregulated in acute myeloid leukemia (AML)
and crucial for maintaining physiological RNA splicing and AML survival. Genetic targeting of one key member
of this network, RBM39, repressed cassette exon inclusion and promoted intron retention within mRNAs
encoding HOXA9 targets as well as in other RBPs preferentially required in AML. Fortuitously, it has recently
been described that a class of clinically validated anti-cancer sulfonamide compounds (including the drugs
indisulam and E7820) mediate RBM39 degradation as their dominant cellular mechanism of action. This
occurs via novel interactions between these compounds and the DCAF15 adapter protein of the CUL4/Ddb1
ubiquitin ligase complex with RBM39 as a neo-substrate. Treatment of AML cells with such compounds in
vitro and in vivo resulted in similar lethal cellular effects due to perturbations in RNA splicing. The effects of
RBM39 loss on splicing resulted in preferential lethality of spliceosomal mutant AML, providing a novel strategy
for treatment of AML bearing recurrent mutations in RBPs that regulated splicing.
Overall these data identify RBM39 as central to a network of functionally and physically interacting RBPs
upregulated in AML over normal hematopoietic precursors and required for AML maintenance. Despite these
insights we do not yet understand the basis for the cell- and context-specific roles of RBM39 in malignant
versus normal hematopoietic cells. We also do not understand the exact mechanisms by which RBM39 loss
results in eradication of AML. We hypothesize that RBM39 is differentially required in malignant versus
normal hematopoietic cells, may be differentially required depending on the precise stage of
hematopoiesis, and will be required for leukemia initiation as well as maintenance. These hypotheses
will be addressed in two Specific Aims. Aim 1 will determine the biological role of RBM39 in normal and
malignant hematopoiesis. In this Aim, we will utilize a novel genetic model for genetic deletion of RBM39 in
vivo in a cell- and time-specific manner to rigorously dissect the roles of RBM39 in malignant versus normal
hematopoietic stem and progenitor cell populations. Aim 2 will identify the mechanistic basis for cell-type and
disease-specific roles for RBM39 in normal and malignant hematopoietic cells. In this Aim we will compare the
direct RNA binding targets and effects of RBM39 loss on splicing across normal and malignant hematopoietic
cells. In addition, we will evaluate a potential novel for RBM39 in transcriptional elongation by the FACT
complex, identified by our preliminary studies as an interact...

## Key facts

- **NIH application ID:** 10408047
- **Project number:** 5R01CA242020-03
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Omar Abdel-Wahab
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $544,735
- **Award type:** 5
- **Project period:** 2020-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10408047

## Citation

> US National Institutes of Health, RePORTER application 10408047, Targeting an RNA Binding Protein Network in Acute Myeloid Leukemia (5R01CA242020-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10408047. Licensed CC0.

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