BCR-ABL1 is the fusion protein born from the Philadelphia chromosome, the hallmark genetic abnormality of chronic myeloid leukemia and a subset of B-cell acute lymphoblastic leukemia. First described in landmark reviews by Goldman and Melo, the fusion fuses the BCR gene on chromosome 22 with the ABL1 tyrosine kinase gene on chromosome 9, producing a constitutively active kinase that drives uncontrolled proliferation and survival of white blood cells. Tyrosine kinase inhibitors were designed to slip into the ATP-binding pocket of ABL1 and freeze the enzyme in an inactive state. In structural studies of the kinase domain, including work by Cowan-Jacob and colleagues, imatinib and related compounds achieve exactly that. And yet, in patients, the kinetics of treatment response are markedly slower than direct enzyme inhibition would predict, an effect sometimes described as target sluggishness.

The new research reframes this sluggishness as an emergent property of how BCR-ABL1 organizes itself inside the cell. Rather than floating freely through the cytoplasm as isolated molecules, the team found that BCR-ABL1 molecules condense into dense, membraneless assemblies reminiscent of liquid droplets. These condensates form through multivalent, weak interactions among intrinsically disordered regions of the protein, the same class of physical chemistry that governs the formation of cellular structures such as nucleoli, stress granules and P bodies. The study connects this condensate behavior directly to therapeutic response: when BCR-ABL1 resides within these droplets, the local molecular environment becomes a physical barricade that slows the entry and action of tyrosine kinase inhibitors.

The concept of phase separation has transformed cell biology over the past decade. In a widely cited 2018 paper in Cell, Qamar and colleagues demonstrated that low-complexity protein domains can undergo liquid-liquid phase separation, creating compartments whose material properties dictate how molecules exchange with the surrounding cytoplasm. The new study applies this framework to cancer signaling for the first time in the context of targeted therapy. The authors showed that disrupting the conditions that promote condensate formation made BCR-ABL1 more accessible to drugs, while conditions that stabilized the droplets exaggerated the sluggish response. The droplet, in effect, functions as a microscopic shelter: drug molecules can reach the droplet surface, but penetrating the dense interior to reach every kinase molecule takes far longer than engaging freely diffusing protein.

Technically, the researchers combined protein biochemistry with cellular assays and clinical material. They purified BCR-ABL1 protein and observed its condensation behavior in solution, finding that the protein spontaneously demixes from the aqueous phase to form spherical droplets that fuse with one another and exchange internal contents, hallmarks of a liquid state. In cells, they visualized BCR-ABL1 condensates and correlated their abundance with the speed and completeness of kinase inhibition after tyrosine kinase inhibitor treatment. Crucially, the team collected bone marrow and blood samples from patients with BCR-ABL1-positive leukemia through collaborations with clinicians at Zhejiang Cancer Hospital and the First Hospital of China Medical University, allowing them to test whether condensate behavior in patient-derived cells tracked with treatment response.

The clinical implications of this reframing are substantial. Resistance to tyrosine kinase inhibitors has traditionally been attributed to kinase domain mutations, most famously the T315I substitution that abolishes imatinib binding, or to the persistence of leukemic stem cells that are intrinsically insensitive to the drugs. Studies such as those by Braun and colleagues and by Schneider and colleagues in Nature Cancer have catalogued the biology of these persistent cells, which survive initial therapy and fuel relapse. The phase separation model adds an entirely orthogonal mechanism: a cell can carry a completely drug-sensitive kinase and still mount a delayed response simply because its target protein is packaged inside droplets that physically exclude or retard drug penetration. This innate, non-genetic sluggishness could explain why a measurable fraction of cells in every treated patient survives the earliest hours and days of therapy without carrying any resistance mutation at all.

The finding also resonates with earlier structural and biochemical work on the ABL1 kinase. Structures of ABL1 bound to imatinib, dasatinib and nilotinib published by Tokarski and colleagues revealed exactly how these compounds lock the kinase in its inactive conformation, and kinetic studies showed rapid association rates in purified systems. The paradox between fast in vitro inhibition and slow cellular response now finds a candidate resolution: the purified enzyme in a test tube has no condensate, no barrier and no sluggishness, while the same enzyme inside a leukemic cell is wrapped in a liquid compartment that throttles drug access. Zhao and colleagues’ early structural characterization of the BCR-ABL1 complex, and Smith and colleagues’ dissection of its signaling architecture, provided the molecular map; phase separation now supplies the cellular geography that shapes how drugs navigate that map.

From a therapeutic standpoint, the study suggests that modulating condensate properties could become a strategy to sensitize leukemic cells to existing drugs. If the physical barrier created by BCR-ABL1 condensates is a principal cause of sluggish drug response, then agents that dissolve or destabilize the droplets, or that alter the material properties of the condensate so that small molecules diffuse through it freely, could accelerate and deepen the effect of tyrosine kinase inhibitors. Conversely, the work raises a caution for drug development: potency measured against purified kinase may systematically overestimate how quickly a compound will work in a cell whose target is phase-separated. Screening platforms that incorporate condensate-relevant conditions could help identify compounds that retain efficacy against droplet-sequestered targets, particularly for B-cell acute lymphoblastic leukemia, where early response kinetics strongly influence long-term outcome, as population studies by Qin and colleagues and reports by Ravandi and Molica have documented.

The broader significance extends beyond a single kinase or a single disease. Cancer biologists have increasingly recognized that many oncogenic proteins contain the disordered, multivalent regions that drive phase separation, and that signaling complexes such as those assembled by fusion oncoproteins, including the EML4-ALK and NUP98 fusions studied by Dixon and colleagues in engineered systems, may exploit condensation to amplify and sustain their signals. The BCR-ABL1 study demonstrates that this same organizational principle can also serve as a defensive architecture against therapy. Pendergast and colleagues’ classic 1991 work showed that BCR sequences activate ABL1 tyrosine kinase; three decades later, the new findings suggest that those same BCR-derived regions may coil the fusion protein into droplets that protect the activated kinase from the drugs designed to silence it.

For patients with chronic myeloid leukemia, tyrosine kinase inhibitors have converted a uniformly fatal disease into a manageable chronic condition, and a minority of patients now attempt treatment-free remission under close monitoring. Yet discontinuation fails in a substantial fraction, and persistent cells endure for years. By exposing the physical mechanism behind innate sluggishness, this research opens a new front in the effort to eliminate residual disease: rather than only designing better inhibitors, oncologists may one day prescribe drugs that strip away the droplet shield itself. The image of a cancer protein hiding inside a liquid droplet is a vivid one, and it captures a larger truth about modern biology. Cancer is not only a disease of genes and pathways but of physical organization, and conquering it may require manipulating not just what proteins do, but where and how they gather inside the cell.

Subject of Research: Phase-separated BCR-ABL1 condensates that delay the response of leukemic cells to tyrosine kinase inhibitor therapy

Article Title: Phase separation drives the innate sluggishness of BCR-ABL1 in response to targeted therapy

Article References: Li, G., Wu, J., He, Z., Zhao, J., Chen, H., Zhou, J., Zhang, Q., Wang, Z., Li, Q., & Jiang, P. (2026). Phase separation drives the innate sluggishness of BCR-ABL1 in response to targeted therapy. Cell Research. https://doi.org/10.1038/s41422-026-01286-w

Image Credits: AI Generated

DOI: 10.1038/s41422-026-01286-w

Keywords: BCR-ABL1, phase separation, chronic myeloid leukemia, tyrosine kinase inhibitors, condensates, imatinib, targeted therapy, leukemia, drug resistance, liquid-liquid phase separation, oncology, cell biology

The physical chemistry underlying condensates is elegant in its simplicity. Multivalent molecules, particularly proteins containing intrinsically disordered regions and repeated interaction motifs, can demix from the surrounding nucleoplasm or cytoplasm when their local concentrations and interaction energies cross a threshold, much like oil droplets forming in water. Early landmark studies demonstrated that germline P granules behave as liquids that localize by controlled dissolution and condensation, and subsequent work established the nucleolus as a multiphase liquid condensate and showed that super-enhancers assemble transcriptional coactivators into phase-separated compartments that link genome organization to gene control. This nucleation landscape is exquisitely sensitive to molecular composition, salt concentration, temperature, pH and post-translational modifications, meaning the cell can tune condensate formation and dissolution with impressive speed and reversibility.

Cancer exploits this tunability. The review synthesizes extensive evidence that aberrant LLPS contributes to tumorigenesis across a striking range of mechanisms. Oncogenic fusion proteins, which arise from chromosomal translocations and are common drivers of sarcomas, leukemias and brain tumors, frequently acquire prion-like low-complexity domains that promote ectopic phase separation, retargeting chromatin regulatory complexes and rewiring transcriptional programs. The BRD4-NUT fusion oncoprotein forms aberrant condensates that hijack the transcriptional machinery in NUT carcinoma, while EML4-ALK condensates in lung cancer and phase-separating NTRK fusions concentrate kinase signaling into cytoplasmic granules that fire oncogenic pathways constitutively. Disease-associated mutations in the phosphatase SHP2 promote phase separation that underlies MAPK hyperactivation, and point mutations in the chromatin reader ENL create condensate-promoting hotspots that drive leukemogenesis in vivo.

Tumor suppressors, too, are entangled with condensate biology, sometimes in paradoxical ways. The tumor suppressor SPOP normally organizes active phase-separated compartments in the nucleus, and cancer mutations disrupt these assemblies, impairing the destruction of oncogenic substrates. The histone demethylase UTX exerts its anti-tumor activity at least in part through condensation, and perturbing TET2 condensation alters genome-wide DNA methylation patterns in leukemia cells. On the oncogenic side, transcriptional co-activators YAP and TAZ, key effectors of the Hippo pathway, use phase separation to compartmentalize transcription machinery, reorganize genome topology and sustain long-term target gene expression, and interferon-gamma-driven YAP condensation has even been implicated in tumor resistance to anti-PD-1 immunotherapy. Stress granules themselves can act as oncogenic platforms, with RIOK1 phase separation restricting PTEN translation in hepatocellular carcinoma and PABPC1 condensates controlling selective translation in chronic myeloid leukemia blast crisis.

The reach of dysregulated phase separation extends into the machinery that governs innate immunity, an interface of growing therapeutic importance. The DNA sensor cGAS undergoes liquid phase condensation upon binding cytosolic DNA, activating type I interferon signaling that can either suppress tumors or, when subverted, promote tumorigenesis. Mutant NF2 induces phase separation that imprisons the cGAS-STING machinery, abrogating anti-tumor immunity, while STING itself acts as a phase-separator that can suppress innate immune signaling. Hypoxia, a defining feature of tumor microenvironments, reshapes the condensate landscape: low oxygen triggers ZHX2 phase separation that alters chromatin looping to drive metastasis, promotes FUS-circRNA stress granules that fuel autophagy in triple-negative breast cancer, and lactate-sensitive enzymes such as AARS1 modify cGAS and p53 through lactylation, tilting condensate dynamics toward tumor progression. Even metabolic states matter, as glycogen accumulation and phase separation have been shown to drive liver tumor initiation.

What elevates this review from a catalogue of mechanisms to a therapeutic manifesto is its detailed treatment of engineering strategies designed to modulate condensates directly. Among the most inventive are D-amino-acid-based interfering peptides, which exploit the protease resistance of mirror-image peptides to infiltrate and disrupt pathological condensates. Short designer peptides have already been shown to disassemble tau fibrils in models of neurodegeneration, and the same logic is being applied to oncogenic droplets. Pharmacological inhibition of SRC-1 phase separation suppresses YAP-driven transcription, targeting androgen receptor phase separation can overcome resistance to antiandrogen therapies in prostate cancer, and dissolution of oncofusion transcription factor condensates has emerged as a viable strategy for fusion-driven malignancies. Recently, targeting FOXM1 condensates reduced breast tumor growth and metastasis in preclinical models, and disruption of the KAT8-IRF1 condensate diminished PD-L1 expression, thereby promoting anti-tumor immunity.

Post-translational modifications offer a second, highly programmable axis of control. Phosphorylation, acetylation, methylation, ubiquitination, SUMOylation, PARylation, O-GlcNAcylation and lactylation each tune the multivalent interactions that drive condensate assembly or dissolution. RNA polymerase II C-terminal domain hyperphosphorylation is itself governed by a phase-separation mechanism, and phosphorylation of HDAC6 drives aberrant chromatin architecture in triple-negative breast cancer. PARP1-mediated poly(ADP-ribosylation) can disrupt condensates to halt global transcription after DNA damage, while sirtuin-sensitive acetylation of TDP-43 drives its pathological phase separation. The review argues that post-translational modification-mimetic approaches, in which engineered molecules co-opt these chemical switches, could allow clinicians to flip condensate states in tumor cells with a specificity that traditional enzyme inhibitors have struggled to achieve against disordered proteins.

Perhaps the most forward-looking section concerns synthetic condensates as drug delivery platforms. Rather than merely dissolving harmful droplets, bioengineers are learning to build benign ones. In situ formation of biomolecular condensates can create intracellular drug reservoirs that augment chemotherapy, while coacervate vesicles assembled through LLPS improve the delivery of biopharmaceuticals, and phase-separating peptides enable direct cytosolic delivery of macromolecular therapeutics with redox-triggered release. Programmable synthetic condensates have been used to enhance translation from target mRNAs and to control cellular behavior, and intrinsically disordered region-induced condensation has improved the cytotoxicity of CAR-T cells against low-antigen cancers. Design of intrinsically disordered region-binding proteins and micropeptide killswitches that probe condensate microenvironments point toward an era in which the chemical milieux inside droplets—differences in polarity, pH and redox state—can be navigated to sharpen drug targeting and overcome resistance.

The authors are candid about the obstacles that separate this vision from routine clinical practice. Condensates lack defined binding pockets, complicating conventional structure-guided drug design, and the same material properties that make them dynamic also make them hard to model computationally. Advances in machine learning predictors such as catGRANULE 2.0, STARLING and PSPire, alongside phase-separation-directed screening and improved microscopy methods, are beginning to close the gap by identifying which condensates exist in a given tumor and which modulators shift their dynamics. The reviewers also emphasize translational design considerations, including how therapeutics partition into nuclear condensates, a factor shown to influence the efficacy of cancer drugs. By integrating biophysical insight with engineering platforms, Wang, Zhang and Zhou outline a conceptual framework in which oncogenic drivers long dismissed as undruggable—disordered transcription factors, fusion oncoproteins, scaffold proteins—can finally be engaged through the physics of their assemblies. If that framework holds up in the clinic, the liquid droplets that cancer co-opted for its own ends may become the very vulnerabilities that defeat it.

Subject of Research: The role of liquid–liquid phase separation and biomolecular condensates in cancer pathogenesis and therapy

Article Title: Biomolecular condensates in cancer therapy

Article References: Wang, B., Zhang, L., & Zhou, F. (2026). Biomolecular condensates in cancer therapy. Nature Reviews Bioengineering. https://doi.org/10.1038/s44222-026-00493-9

Image Credits: AI Generated

DOI: 10.1038/s44222-026-00493-9

Keywords: biomolecular condensates, liquid-liquid phase separation, cancer therapy, LLPS, oncogenic fusion proteins, interfering peptides, synthetic condensates, drug delivery, post-translational modifications, tumor suppressors, Hippo-YAP signaling, bioengineering