About

Omar Abdel-Wahab, MD, is the Chair of the Molecular Pharmacology Program at Sloan Kettering Institute (SKI) and an Attending Physician on the Leukemia Service in the Department of Medicine at Memorial Sloan Kettering Cancer Center. He studies the functional genomics of hematopoietic malignancies, focusing on understanding the molecular mechanisms underlying blood cancers. Dr. Abdel-Wahab holds the Evnin Family Chair in Molecular Pharmacology and has been recognized for his significant contributions to cancer research, including being elected to the National Academy of Medicine. His laboratory research explores innovative approaches such as cellular immunotherapy for treating aggressive forms of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). He is also involved in investigating the genetic and molecular basis of leukemia, including the role of splicing factor mutations and their implications for targeted therapies.

Selected publications

• Finding an Achilles’ heel of cancer cells: Exonized Alu elements in AURKA

  Molecular Cell · 2026-01-01

  articleSenior author
  PublisherDOI

• Inherited resilience to clonal hematopoiesis by modifying stem cell RNA regulation

  Science · 2026-01-01 · 4 citations

  articleOpen access

  Somatic mutations that increase the fitness of hematopoietic stem cells (HSCs) drive their expansion in clonal hematopoiesis (CH) and predispose individuals to blood cancers. Population variation in the growth rate and potential of mutant clones suggests that genetic factors may confer resilience against CH. Here, we identified a noncoding regulatory variant, rs17834140-T, that protects against CH and myeloid malignancies by selectively down-regulating the RNA-binding protein MSI2 in HSCs. By modeling variant effects and mapping MSI2 binding targets, we uncovered an RNA network that maintains human HSCs and influences CH risk. Variant rs17834140-T was associated with slower CH expansion, and stem cell MSI2 levels modified ASXL1 -mutant HSC clonal dominance. These findings leverage natural resilience to illuminate posttranscriptional regulation in human HSCs, suggesting that inhibition of MSI2 or its targets could be rational strategies for blood cancer prevention.

  PublisherOA PDFDOI

• Abstract B069: Understanding tumorigenesis and identifying therapeutic targets in CDK12-mutant prostate cancer

  Cancer Research · 2026-01-20

  article

  Abstract Cyclin-dependent kinase 12 (CDK12), a transcription-associated cyclin-dependent kinase (tCDK) is a tumor suppressor in prostate cancer, with biallelic loss observed in ∼1% of newly diagnosed and ∼5% of castration-resistant prostate cancer (CRPC) cases. CDK12-lost tumors are aggressive and are associated with poorer survival and rapid progression to castration resistance. CDK12 functions are essential for cell viability, limiting the mechanistic studies of its loss-of -function. In tumors, its loss is characterized by unique genomic features, notably large tandem duplications on a largely diploid background. As a tCDK, CDK12 phosphorylates RNA polymerase II and regulates transcriptional elongation and processivity. Genetic depletion or inhibition of CDK12 causes aberrant splicing, premature polyadenylation, and transcriptional termination, particularly affecting genes in the homologous recombination (HR) pathway. These defects provided a rationale for therapies such as PARP inhibitors or immune checkpoint blockade, but clinical trials have largely failed. Thus, we hypothesized that tumor cells evolve compensatory mechanisms to sustain CDK12 loss, possibly by engaging another tCDK. To better recapitulate the chronic effects of CDK12 loss observed in tumors, we utilized patient-derived organoid (PDO) models with established CDK12 loss for our studies. Using these models, we evaluated the growth-inhibitory response of CDK12-deficient PDOs to selective inhibitors targeting various transcription-associated CDKs. Notably, we found that all the CDK12-lost PDOs (n=4) were exceptionally sensitive to THZ531, an inhibitor targeting CDK12 and CDK13 (a paralog of CDK12). Next, we analyzed the global transcriptional/co-transcriptional processes in CDK12-lost and CDK12-intact models at baseline and following treatment with THZ531. Mechanistically, we found that THZ531 treatment induced increased splicing errors in CDK12-deficient organoids compared to CDK12-intact controls. The most frequent splicing aberrations were seen in intron retention and exon skipping. These findings indicate that CDK13 plays a compensatory role in maintaining transcriptional and splicing homeostasis in CDK12-deficient settings, and that targeting CDK13 represents a potential therapeutic strategy for this aggressive prostate cancer subtype. Citation Format: Shipra Shukla, Dana Schoeps, Nicholas Terri, Jahan Rehman, Omar Abdel-Wahab, Yu Chen. Understanding tumorigenesis and identifying therapeutic targets in CDK12-mutant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr B069.

  PublisherDOI

• Targeting <i>EZH2</i> Oncogenic Splicing: Decoding the Regulatory Network and Antisense Correction

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-08

  articleOpen access

  Abstract Recurrent mutations in splicing factors (SFs) have been established as crucial drivers of tumorigenesis in several types of blood cancer, and also common in a variety of solid tumors. Mutations change the RNA-binding preferences of SFs, promote global splicing alterations, and often generate erroneous mRNAs that are then degraded by nonsense-mediated mRNA decay (NMD). Consequently, several critical genes linked to hematopoiesis are dysregulated, leading to blood cancer. Although the field has progressed considerably in identifying aberrant genes and affected pathways, effective therapies have not yet emerged in SF-mutated cancers. To address this key gap, we instigated a gene-specific targeted strategy by unlocking the regulatory network. As a proof-of-concept, we scrutinized a tumor suppressor gene EZH2 , which is a bona fide target in SRSF2-mutated cancer. We precisely defined splicing cis-elements in EZH2 transcripts and illustrated the dynamic choreography of regulatory proteins in the entire splicing and NMD catalytic pathways. We uncovered a highly coordinated cross-regulation between splicing and NMD promoted by mutant SRSF2 by enhancing the deposition of critical spliceosome- and NMD-associated factors, augmenting mRNA decay to ablate tumor suppression. We then designed antisense oligonucleotides (ASOs) targeting important regulatory sites. Our lead ASO successfully corrects aberrant splicing and NMD, restores the expression and function of EZH2, and partially rescues hematopoietic defects and cellular properties. Our study demonstrates that ASO pharmacology is an actionable strategy for clinical development, challenging the existing paradigms in SF-mutated cancers.

  PublisherOA PDFDOI

• Outstanding Questions to Understand and Target Splicing Factor–Mutant Blood Cancers

  Blood Cancer Discovery · 2026-04-21

  articleOpen accessSenior author

  Mutations in genes encoding RNA splicing factors are common in patients with myeloid malignancies and chronic lymphocytic leukemia. In this commentary, we discuss key unanswered questions on the causal role of these mutations in blood cancers and precursor conditions as well as efforts to develop therapies targeting these high-frequency neomorphic mutations.

  PublisherOA PDFDOI

• Synergistic intragenic epigenetic deregulation by IDH2 and SRSF2 mutations causes mis-splicing of key transcriptional regulators

  Science Advances · 2026-01-02

  articleOpen access

  Genes affecting DNA methylation (DNAme) are frequently comutated with splicing factors in acute myeloid leukemia (AML) and associate with more aggressive phenotypes. To elucidate the underlying molecular mechanisms, we deeply profiled wild-type and IDH2 R140Q /SRSF2 P95 single- or double-mutant AMLs. We find a unique set of mis-spliced genes and differentially methylated CpGs in double mutants. Mis-spliced exons are enriched in CCNG splicing enhancers and in the corresponding DNAme changes. Using a machine learning model, we can accurately predict exon inclusion levels from proximal CpGs. These CpGs are more likely to overlap footprints of RNA binding and chromatin-modifying complexes but not transcription factors. We also report unique gene expression profiles associated with each genotype; however, the differentially expressed genes do not overlap with mis-spliced transcripts. Instead, the mis-spliced genes encode for proteins that interact with the complexes regulating these differentially expressed genes. Thus, aberrant DNAme and splicing lead to the mis-splicing of key regulatory complexes, resulting in the aberrant gene expression profiles characteristic of these AMLs.

  PublisherDOI

• Sequence-dependent splicing dysregulation drives therapy resistance in pediatric AML

  Cell Reports Medicine · 2026-01-01

  articleOpen access

  Despite improvements in pediatric acute myeloid leukemia (AML) prognosis, about 30% of patients relapse after initial chemotherapy and have poor survival. However, the genetic basis of resistance remains unclear for most patients. To better understand the mechanistic basis and overcome treatment resistance, we analyze RNA sequencing (RNA-seq) data from 702 pediatric AML patients. This effort uncovers a sequence-dependent splicing dysregulation in 36% of children linked to worse prognosis and a lower rate of complete remission. Surprisingly, this change in RNA splicing matches that induced by SRSF2 mutations, which are common in adult AML. Instead, we identify U2AF2 dysregulation as the driver of aberrant splicing in pediatric AML. The pathologic splicing changes are characterized by “weak” polypyrimidine tracts and are susceptible to modest U2AF2 reduction. These outcomes can be improved by pharmacologic modulation of PRMT enzymes. Overall, these findings highlight the importance of modulating splicing defects to improve treatment response in pediatric AML. • Sequence-dependent splicing defects occur in 36% of pediatric AML • U2AF2 downregulation drives aberrant splicing in pediatric AML • Weak polypyrimidine tracts increase sensitivity to U2AF2 loss • PRMT inhibition partially restores splicing and improves treatment response Huang et al. show that 36% of pediatric AML patients harbor sequence-dependent splicing defects that resemble those driven by splicing factor mutations in adult AML. They identify U2AF2 downregulation as the key driver linked to treatment resistance and highlight PRMT inhibition as a potential strategy to restore splicing dysregulation.

  PublisherDOI

• Supplementary Figures S1-S7 from Systematic Evaluation of GAPs and GEFs Identifies a Targetable Dependency for Hematopoietic Malignancies

  2025-12-02

  articleOpen access

  &lt;p&gt;Supplemental Figure 1. Systematic domain-focused CRISPR screens of GAPs and GEFs and transcriptomic profiling identify ARHGAP45 as a hematologic malignancy-biased dependency linked to distinct genetic and risk subgroups. Supplemental Figure 2. ARHGAP45 is a selective dependency in hematopoietic malignancies, but dispensable for normal CD34+ hematopoietic stem/progenitor cells (HSPCs) in vivo. Supplemental Figure 3. ARHGAP45 regulates cell cycle and constrains AML differentiation. Supplemental Figure 4. ARHGAP45 suppresses RhoA activity, and hyperactivation of RhoA suppresses AML growth. Supplemental Figure 5. Loss of ARHGAP45 sensitizes AML to CDC42 inhibition. Supplemental Figure 6. Activity of CAR-like TCRs against ARHGAP45 derived HA-1H antigen in myeloid malignancies. Supplemental Figure 7. In vivo efficacy of CAR-like TCRs against AML cell lines or patient-derived xenograft (PDX) expressing HA-1H.&lt;/p&gt;

  PublisherDOI

• Supplementary Figure S3 from Overlaid Transcriptional and Proteome Analyses Identify Mitotic Kinesins as Important Targets of Arylsulfonamide-Mediated RBM39 Degradation

  2025-11-27

  articleOpen access

  &lt;p&gt;Supplementary Figure S3&lt;/p&gt;

  PublisherDOI

• Supplementary Figure S4 from Overlaid Transcriptional and Proteome Analyses Identify Mitotic Kinesins as Important Targets of Arylsulfonamide-Mediated RBM39 Degradation

  2025-11-27

  articleOpen access

  &lt;p&gt;Supplementary Figure S4&lt;/p&gt;

  PublisherDOI

Labs

• The Omar Abdel-Wahab LabPI

Awards & honors

• Paul Marks Prize for Cancer Research
• National Academy of Medicine