Selected Publications

Cosgun KN, et al. Nature Cancer 7(1):150–168 (2026)

β-catenin is a central component of canonical Wnt signaling and frequently acts as an oncogenic driver in solid tumors through activation of MYC-dependent transcription. Surprisingly, we found that B-cell acute lymphoblastic leukemia (B-ALL) lacks the recurrent mutations that stabilize β-catenin in solid tumors and instead depends on constitutive β-catenin degradation.

Mouse and human B-ALL cells expressed unusually low levels of β-catenin protein, which was constitutively phosphorylated by GSK3β and targeted for proteasomal degradation. Rather than forming transcriptionally active TCF–β-catenin complexes, the residual β-catenin in B-ALL cells associated with the B-cell transcription factor Ikaros and NuRD complex components, resulting in repression of MYC and promoting acute cell death when β-catenin accumulated.

We found that pharmacological inhibition of GSK3β disrupted β-catenin degradation and induced cell death in B-ALL cells. CRISPR-based screens confirmed β-catenin degradation as a central mechanistic target of established GSK3β inhibitors, and GSK3β inhibition showed therapeutic activity in patient-derived xenograft models. These findings uncover an unexpected dependency of B-ALL on β-catenin degradation and provide a rationale for repurposing clinically evaluated GSK3β inhibitors for the treatment of refractory B-cell malignancies.

Lee J*, Ruifeng S*, et al. Sci Signal 19(924):eadw5054 (2026)

Oncogenic tyrosine kinases drive a major subset of acute leukemias, including B-ALL and AML, but the mechanisms that prevent excessive signaling and maintain signaling homeostasis in leukemia cells have remained poorly understood. We identified CD25 as a central component of a dynamic feedback loop that regulates oncogenic tyrosine kinase signaling in acute leukemia.

CD25 expression is associated with active oncogenic tyrosine kinase signaling and marked quiescent leukemia cell state with increased resistance to chemotherapy. Genetic deletion of CD25 reduced leukemia-cell fitness, colony formation and leukemia-initiation capacity in mouse and patient-derived xenograft (PDX) models. Mechanistically, oncogenic tyrosine kinase signaling induced NF-κB-dependent CD25 expression, while PKCδ-mediated phosphorylation of the CD25 cytoplasmic tail stabilized CD25 at the cell surface.

Phosphorylated CD25 recruited inhibitory phosphatases including PTPN6 and INPP5D through a PKCδ- and RACK1-dependent signaling complex, providing negative feedback that restrained oncogenic tyrosine kinase signaling. Disruption of this feedback loop resulted in hyperactivated signaling activities and impaired leukemia-cell fitness. Finally, therapeutic targeting of CD25 with an antibody-drug conjugate induced complete remission in a PDX model of relapsed B-ALL.

These findings reveal a previously unrecognized negative feedback mechanism of oncogenic tyrosine kinase signaling in acute leukemia and identify CD25 as an actionable therapeutic target.

Lee J, Robinson ME, Ma N, Artadji D, Ahmed MA, Xiao G, Sadras T, Deb G, Winchester J, Cosgun KN, Geng H, Chan LN, Kume K, Miettinen TP, Zhang Y, Nix MA, Klemm L, Chen CW, Chen J, Khairnar V, Wiita AP, Thomas-Tikhonenko A, Farzan M, Jung JU, Weinstock DM, Manalis SR, Diamond MS, Vaidehi N & Müschen M. Nature 588:491-497 (2020).

B-cell activation and acute activation of oncogenes induce dramatic changes of cell membrane lipid composition, including >40-fold increases of PIP3-concentrations within seconds. To elucidate the mechanistic and structural requirements for PIP3 accumulation during normal B-cell activation and acute oncogenic transformation, we identified PIP3-interacting proteins by cell-surface proteomic analyses. In addition to proteins known to bind PIP3 with their pleckstrin homology (PH) domain, we identified the short 133-aminoacid protein IFITM3 (interferon-inducible transmembrane protein 3) with the greatest enrichment. Among known cell membrane lipids, PIP3 has the highest negative charge. Instead of a PH-domain, IFITM3 laterally sequestered PIP3 through electrostatic interactions with two basic lysine residues (K83 and K104) located at the membrane–solution interface.

IFITM3 was previously identified as endosomal protein that blocks viral infection. Analyses on gene expression data from patients with B-cell leukemia and lymphoma identified IFITM3 as a particularly strong predictor of poor clinical outcome. In normal resting B-cells, Ifitm3 was minimally expressed and mainly localized in endosomes. However, B-cell activation and oncogenic kinases induced phosphorylation at IFITM3-Y20, resulting in massive accumulation at the cell surface. Ifitm3¯/¯ naïve B-cells developed at normal numbers; however, germinal center formation and production of antigen-specific antibodies were compromised. Oncogenes that induce development of leukemia failed to transform Ifitm3¯/¯ B-cells. Conversely, the phospho-mimetic IFITM3-Y20E induced oncogenic PI3K-signaling and initiated transformation of pre-malignant B-cells. In Ifitm3¯/¯ B-cells, lipid rafts were depleted of PIP3, resulting in defective expression of >60 lipid raft-associated surface receptors and impaired PI3K-signaling. We conclude that phosphorylation of IFITM3 upon B-cell activation induces a dynamic switch from antiviral effector functions in endosomes to PI3K-amplification at the cell-surface. IFITM3-dependent amplification of PI3K-signaling is critical to enable rapid expansion of activated B-cells. In addition, multiple oncogenes depend on IFITM3 to assemble PIP3-dependent signaling complexes and amplify PI3K-signaling for malignant transformation.

Chan LC, Murakami MA, Caeser R, Hurtz C, Kume K, Sadras T, Shojaee S, Hong C, Pölönen P, Nix MA, Ugale A, Chen Z, Lee J, Cosgun KN, Geng H, Chen CW, Chen J, Vogt A, Heinäniemi M, Lohi O, Wiita AP, Izraeli S, Weinstock DM & Müschen M. Nature 583: 845-851 (2020)

Cells often acquire hundreds of mutations before they develop characteristics of cancer. The concept of multi-step cancer progression suggests that the acquisition of mutations in addition to an existing set of mutations invariably accelerates tumor-progression. Studying how oncogenic drivers across multiple signaling pathways interact in 1,148 patient-derived B-cell leukemia samples, we found that individual mutations did not promote leukemogenesis unless they converged on one single oncogenic pathway. Oncogenic drivers that were not aligned with the central oncogenic driver and instead promote growth and survival in divergent directions were only found in 3% of leukemia samples (P=2.2E-16). Even in rare cases of co-occurrence in the same sample, single-cell mutation and phosphoprotein analyses revealed that non-aligned mutations were mutually exclusive and reflected two competing clones.

Genetic reactivation of divergent (suppressed) pathways engaged opposing biochemical and transcriptional programs, causing ‘friction’ with the principal oncogenic driver and subverted malignant transformation. Conversely, Cre-mediated deletion of divergent pathway components precipitated tumor-initiation and accelerated development of fatal, drug-resistant leukemia. Thus, the persistence of divergent signaling pathways represents a powerful barrier to overt malignant transformation.

We propose that a diverse spectrum of signaling input reflects interactions of normal cells with their environment, while convergence on one centralized pathway is characteristic of cancer. Tracking early stages of leukemia-initiation, we identified convergence on one principal oncogenic driver and inactivation of diverging pathways as an early critical step. Pharmacological reactivation of divergent signaling pathways to blunt transformation was achievable by kinase-agonists. Proof-of-concept studies in patient-derived leukemia cells revealed that pharmacological reactivation of suppressed divergent circuits can be leveraged as a previously unrecognized strategy to achieve long-term remission of leukemia and to overcome drug-resistance. Pharmacological pathway reactivation restores a diverse spectrum of signaling input just as in normal cells and creates a signaling environment that is not permissive to transformation.