Biology subjects

Bagchi, A.

Publications and source records attributed to Bagchi, A..

At least 19 recordsLinked to original sources

bioRxiv2026

KH1 Domain of Poly C Binding Protein 1 (PCBP1) Interacts with Utrophin-A mRNA and Modulates Utrophin-A Expression in Mouse Myoblasts

Utrophin upregulation is an attractive strategy to ameliorate Duchenne Muscular Dystrophy (DMD). Here, we investigated whether the murine poly(C)-binding protein 1 (PCBP1) directly interacts with the utrophin-A mRNA, and how the interaction shapes the fate of utrophin-A in muscle cells. As no experimentally validated structure of the murine PCBP1 is available, AlphaFold2 was utilized to predict the structure of the full-length protein and the KH1-KH2 domain of the protein. The more stable and reliable model of the KH1-KH2 domain of PCBP1 was then docked with the 5'UTR of the utrophin-A mRNA, and the top-ranked docked complex was utilized for MD simulation to identify the most stable hydrogen bond-forming amino acid residues from PCBP1. ITC showed a thermodynamically favorable spontaneous interaction between the full-length PCBP1 and the 5'UTR of utrophin-A mRNA, but the deletion mutant of PCBP1, lacking the predicted contact region, failed to exhibit any interaction. This observation was also confirmed by an RNA-immunoprecipitation assay in C2C12 cells. However, the mutant PCBP1 was unable to alter the expression of the utrophin-A in the C2C12 cells. In cells, PCBP1 overexpression lowered utrophin-A expression, while shRNA knockdown produced reciprocal increases. A 5'UTR-luciferase reporter mirrored this observation. Finally, subcellular fractionation showed that PCBP1 promotes nuclear retention of utrophin-A transcripts and reduces their cytoplasmic availability, with reciprocal shifts upon PCBP1 knockdown. Considering earlier work on PCBP2, our data suggest both paralogs recognize the same 5'UTR element, and the KH1-dependent interaction represses utrophin-A by coupling nuclear retention to reduced protein output. Thus, the PCBP1-5'UTR interaction emerges as a potent target for utrophin de-repression in DMD.

molecular biology↗

bioRxiv2026

Recursive feedback between Piezo1 conformation and membrane mechanics drives self-organization into finite clusters

Piezo1 is a major mechanosensitive ion channel through which cells convert physical force into calcium-dependent signaling programs. In living membranes, this conversion depends not only on channel activation, but also on whether Piezo1 channels remain dispersed, assemble into finite clusters, or concentrate at sites where receptor signaling and mechanical forces reorganize the membrane. How single-channel force sensing is amplified into these collective spatial states remains unknown. Here we identify a membrane-feedback mechanism that converts single-channel mechanosensing into self-organized Piezo1 clusters. Coupling channel shape to membrane-cortex elasticity reveals that neighboring channels relax shared deformation fields, generating an effective interaction with short-range attraction opposed by longer-range repulsion. As channel density or membrane tension increases, this balanced interaction shifts Piezo1 from dispersed channels into mesoscale finite clusters. Brownian-dynamics simulations reproduce experimentally observed Piezo1 cluster geometries and swelling-induced cluster growth, while comparisons across distinct cellular systems place Piezo1 organization within a common density-tension framework. Applying the same mechanism to LPS-activated macrophages shows how receptor-induced membrane reorganization locally concentrates Piezo1 above the clustering threshold. Overall, these results recast Piezo1 mechanotransduction from isolated-channel force sensing to a membrane-driven self-organization process that spatially biases force-dependent calcium signaling within cells.

biophysics↗

bioRxiv2025

Interferon Restores Antigen Presentation and Sensitizes Medulloblastoma to T Cell Killing

Medulloblastomas are commonly considered immunologically cold and refractory to immunotherapy. One contributing factor to their low immunogenicity is impaired antigen presentation, which allows tumor cells to escape from cytotoxic T cells. Here we use a syngeneic mouse model of medulloblastoma to study the role of CD8+ T cells in medulloblastoma growth. We demonstrate that despite low expression of MHC Class I on tumor cells, depletion of CD8+ T cells accelerates tumor growth, whereas adoptive transfer of tumor-reactive CD8+ T cells prolongs survival. These anti-tumor effects rely on T cells secreting interferon gamma (IFN{gamma}), which induces MHC class I on tumor cells and facilitates tumor cell killing by T cells. Notably, this response is essential for CD8+ T cell-mediated tumor attack, as blocking IFN{gamma} signaling in vivo abrogates MHC class I induction and eliminates the beneficial effect of T cells. Importantly, delivering IFN{gamma} directly into tumors via convection-enhanced delivery (CED) enhances CD8+ T cell-mediated killing of tumor cells and significantly prolongs survival in tumor-bearing mice. These studies highlight the importance of T cells in controlling brain tumor growth and the value of IFN{gamma} as an adjuvant for T cell-based immunotherapy.

cancer biology↗

bioRxiv2025

CD155 regulates tumor growth and immune evasion in diffuse midline glioma.

Diffuse midline glioma (DMG) is a devastating pediatric brain tumor with an unmet need for novel therapies. Immune checkpoint inhibitors have failed to prolong survival for DMG patients. In this study, we analyzed the expression of immune checkpoint molecules in human and murine DMG cells, as well as primary brain tumor samples, and identified CD155 as the most highly expressed. When murine DMG cells were co-cultured with CD8+ T cells, silencing of CD155 led to a marked increase in T cell-mediated killing. Strikingly, CD155-deficient DMG cells failed to grow in immunocompetent mice, and depletion of CD8+ T cells allowed these tumors to grow. CD155 also exerted cell-autonomous effects on tumor cells: silencing of CD155 led to induction of apoptosis of DMG cells and to delayed tumor growth in immunodeficient mice. Transcriptomic analyses identified FOXM1 as a key target of CD155. Notably, FOXM1 silencing also led to reduced proliferation of DMG cells in vitro and in vivo. Finally, treatment of DMG-bearing mice with Thiostrepton, a FOXM1-targeting agent, delayed tumor growth and prolonged survival. These studies demonstrate that CD155 regulates immune evasion and tumor growth in DMG, and suggest that targeting CD155 could be a valuable two-pronged therapeutic strategy for this disease. Conflict-of-interest statementThe authors have declared that no conflict of interest exists.

cancer biology↗

bioRxiv2024

Macropinocytosis controls metabolic stress-driven CAF subtype identity in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) tumors are deficient in glutamine, an amino acid that tumor cells and CAFs use to sustain their fitness. In PDAC, both cell types stimulate macropinocytosis as an adaptive response to glutamine depletion. CAFs play a critical role in sculpting the tumor microenvironment, yet how adaptations to metabolic stress impact the stromal architecture remains elusive. In this study, we find that macropinocytosis functions to control CAF subtype identity when glutamine is limiting. Our data demonstrate that metabolic stress leads to an intrinsic inflammatory CAF (iCAF) program driven by MEK/ERK signaling. Utilizing in vivo models, we find that blocking macropinocytosis alters CAF subtypes and reorganizes the tumor stroma. Importantly, these changes in stromal architecture can be exploited to sensitize PDAC to immunotherapy and chemotherapy. Our findings demonstrate that metabolic stress plays a role in shaping the tumor microenvironment, and that this attribute can be harnessed for therapeutic impact. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=173 SRC="FIGDIR/small/625709v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@40b38eorg.highwire.dtl.DTLVardef@1cc6a3borg.highwire.dtl.DTLVardef@15283e8org.highwire.dtl.DTLVardef@5214d2_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

The Hidden Potential of PDE4 Inhibitor Rolipram: A Multifaceted Examination of its Inhibition of MMP2/9 Reveals Theraputic Implications

A PDE4 inhibitor, Rolipram, was previously found to down-regulate (in a manner dependent on cAMP-PKA) MMP2 and MMP9 levels, important markers of epithelial-to-mesenchymal transition in human breast cancer cell lines. However, zymographic studies revealed that rolipram could also alter the enzymatic activities of these MMPs, even in the presence of the PKA inhibitor H89. This calls for more detailed investigations of the inhibitory mechanism of rolipram on MMP2 and MMP9. The prediction of ligand-based targets through online reverse screening indicated that proteases are likely targets of rolipram. Computational molecular docking also demonstrated significant binding affinities of rolipram for both MMP2 and MMP9 proteins. Concurrently, a well-known inhibitor of MMPs, SB3CT, was utilized as a positive control for this study. The best models of the docked complexes were used as initial conditions for molecular dynamics (MD) simulations to explore their dynamic behavior and stability. In particular, both the MMP2-rolipram and MMP9-rolipram complexes were found to be stable and compact for the duration of the simulation (300 ns). Several stable hydrogen bonds were also detected between the proteins and rolipram. In vitro experiments using primary cells from patients with breast cancer also showed that rolipram could alter the enzymatic activities of MMP2 and MMP9, independent of the cAMP-PKA signaling pathway. These observations indicate the ability of rolipram to control breast cancer by regressing the functions of MMP2 and MMP9, thus having off-targets other than PDE4 to have direct control over proteins that are involved in the advancement of metastasis.

cancer biology↗

bioRxiv2024

Designing Combinatorial Multiepitope Vaccine Candidates against Scrub Typus by a Proteome-wide Immunoinfomatics Approach.

Scrub typhus (ST) is a mite-borne infection caused by the bacteria Orientia tsutsugamushi and a major public health concern in eastern and south eastern Asia. Early diagnosis and immediate intervention with antibiotics are required to limit the severity of the infection. Prophylaxis is compromised by the absence of an effective vaccine against O. tsutsugamushi. Development an effective vaccine is impeded due to extreme divergence of major surface antigens limiting cross-protectivity. Adopting a proteome-wide immunoinformatic approach, here, immunodominant outer membrane proteins are identified and conserved regions enriched in B-cell, Tc-cell, and Th-cell epitopes were mapped. Similarly, immunodominant stretches from salivary proteins of the vector were identified. Fifteen independent MEVs were designed by combining such segments and were analysed for physicochemical and immunological properties. Tertiary structure of the prioritized MEV was modelled, and interaction with TLR2, 4, and 5 was profiled through molecular docking and MD simulation. A glycosylation-deficient version of the MEV was also designed and analysed similarly. Both the MEVs were immune-simulated, which indicated elicitation of effective immune response. In silico cloning and expression were performed for bacterial and mammalian expression systems. Though the proteome-wide combinatorial approach with immunodominant segments demonstrated prospect, experimental validation for its efficacy against ST is warranted.

bioinformatics↗

bioRxiv2024

PDE4 inhibitor Rolipram represses hedgehog signaling via ubiquitin-mediated proteolysis of GLI transcription factors to regress breast cancer

Aberrant activation of the hedgehog signaling pathway positively correlates with progression, invasion and metastasis of several cancers, including breast cancer. Although numerous inhibitors of the Hedgehog signaling pathway are available, several oncogenic mutations of key components of the pathway, including Smoothened (Smo), have limited their capability to be developed as putative anti-cancer drugs. In this study, we have modulated the Hedgehog signaling pathway in breast cancer cell lines and tumor-bearing BALB/c mice, using a specific phosphodiesterase 4 (PDE4) inhibitor rolipram. The results indicated that increased levels of cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA), due to the treatment with rolipram on MCF-7 and MDA-MB-231 cells, induced PKA-mediated ubiquitination of Glioma-associated oncogene homolog 2 full length (GLI2FL) and GLI3FL, leading to their transformation to respective repressor forms. This in turn reduced the level of Glioma-associated oncogene homolog 1 (GLI1) transcription factor in a time-dependent manner. We have also shown that elevated level of PKA reduced the level of phosphorylated glycogen synthase kinase 3{beta} (GSK3{beta}), which is known to augment PKA-mediated phosphorylation of GLI2FL and GLI3FL. Rolipram also significantly altered the wound healing capability as well as key markers of wound healing in MCF-7 and MDA-MB-231 cells. Moreover, rolipram caused significant reduction in tumor weight and volume in tumor-bearing mice model. The histological analysis revealed significant reduction in the number of multi-nucleated cells in tumor tissue and substantially reduced levels of cellular infiltration in the lung of rolipram treated tumor-bearing mice. Rolipram also reduced the levels of GLI1 in tumor-bearing mice by enhancing the PKA levels. Therefore, it may be concluded that rolipram can be used as an effective inhibitor of Hedgehog signaling pathway downstream of Smo to control breast cancer progression and metastasis in both hormone-responsive and triple negative breast cancers.

cancer biology↗

bioRxiv2024

Repurposing approved protein kinase inhibitors as potent anti-leishmanials targeting Leishmania MAP kinases

Leishmaniasis is a vast array of chronic diseases caused by the protozoan parasite of the genus Leishmania transmitted by the sandfly belonging to the genus Phlebotomus (Old World) and Lutzomyia (New World). Among the various factors that contribute to the virulence and pathogenesis of the disease, protein kinases play crucial role in modulating the parasites biology in the host system. There are no specific drugs identified to treat the disease specifically. Moreover, resistance against approved anti-leishmanials has made it important to look for a few pre-clinical candidates against visceral leishmaniasis. MAP kinase is one such candidate of protein kinase family that regulates cell proliferation in eukaryotes. In this study, we have identified 23 MAPKs from Leishmania genome and have screened 12 FDA approved protein kinase inhibitors against those MAPKs in search of a potential lead for new drug exploration. Among the inhibitors, sorafenib and imatinib have been identified as potential drug candidates based on multiple criteria including binding affinity, ADME scores, absorption and their ability to cross blood-brain barrier. Furthermore, these drugs showed excellent anti-proliferative effects in Leishmania promastigotes, resulted in change of cell morphology, flagellar length, promoted cell cycle arrest through ROS generation and reduced intra-macrophage parasitic burden. Collectively, these results imply involvement of MAP kinases in infectivity and survival of the parasite and can pave the avenue for repurposing sorafenib and imatinib as anti-leishmanial agents.

bioinformatics↗

bioRxiv2023

An in-silico approach to study the molecular interaction of the PINK1 kinase domain with Parkin Ubl domain

Parkinsons Disease (PD) is the second most common neurodegenerative disorder which creates devastating effects on the neurons of the mid brain. PARK2 and PARK6 genes encode the E3 ubiquitin ligase Parkin and serine/threonine protein kinase PINK1 (PTEN-induced kinase 1), respectively. Mutations in these proteins are responsible for majority of the early onset of PD. PINK1 protein along with Parkin are known to participate in the mitochondrial mitophagy pathway which selectively removes damaged mitochondria. Parkin with the help of its intra-domain interactions goes to an autoinhibited inactive state. Parkin ubiquitin activity is suppressed in this condition. Phosphorylation of the Serine65 residue, present in the Ubl domain of Parkin, is required for its ubiquitin ligase activity. PINK1 protein phosphorylates the Serine65 residue after its self-phosphorylation. After activation, Parkin protein ubiquitinates other damaged mitochondrial proteins for their degradation. Therefore, PINK1-Parkin interaction is important for the proper maintenance of the mitochondrial and neuronal fidelity. In this present work, we are trying to find out how the mutations in the PINK1 kinase domain would affect the modes of its interaction with the Ubl domain of Parkin. We used the three dimensional coordinates of the PINK1 and Ubl domain of Parkin from our previous work and selected the mutations P296L and G309D which have the abilities to hamper the said interactions between PINK1 and the Ubl domain of Parkin. We used molecular docking followed by molecular dynamics simulations to study the nature and structural dynamics of the binding interactions. The results from our study could provide an insight into the PINK1 mediated Parkin activation and plausible biochemical mechanism behind the onset of PD.

bioinformatics↗

bioRxiv2023

Molecular insight into the mechanism of action of some beneficial flavonoids for the treatment of Parkinson's Disease

Parkinsons Disease (PD) is a severe neurodegenerative disorder. It is characterized by the declination of dopaminergic (DA) neurons of substantia nigra pars compacta in the mid brain. Decrease in dopamine level in substantia nigra is a major event in PD. Mutation in Parkin protein is responsible for the onset of Autosomal Recessive Juvenile Parkinsons (ARJP) Disease. Till date, there is no available treatment of PD without any side-effects. Therefore, the focus has been shifted to identifying natural product inhibitors for the treatment of the disorder. Flavonoids, a class of natural products, have proven neuroprotective effects. Some of the flavonoids have their abilities to influence the activities of central nervous system. Therefore, many studies are being conducted to analyze their activities to lower the progression of neurodegenerative diseases. This study was conducted to identify the flavonoids to be used as potential drugs for PD. From the literature, we picked up the flavonoids active on the nervous systems of human beings. We employed a literature mining approach to build a Structure Activity Relationship (SAR) to measure their efficacies. We performed molecular docking simulations using the flavonoids as the ligands and computed their binding free energy values. Our study would therefore point towards future drug- designing endeavours to come up with plausible therapeutics against PD onset.

bioinformatics↗

bioRxiv2023

Comprehensive codon usage analyses of the mutations in the Parkin protein leading to Parkinsonism

Neurodegenerative diseases typically occur due to the abnormal behavior of the proteins. One of the most prevalent neurodegenerative diseases is the Parkinsons disease. Parkin protein encoded by PARK2 gene is the central player in the central nervous system. Mutations in Parkin lead to the onset of Parkinsonism. In this work, we made an attempt to decipher the codon usage patterns of the amino acid residues in the different domains of Parkin protein. We observed that mutations at the first two codon positions have statistically significant disease associations. This is the first such report that analyzes the correlation between the disease severity of Parkinsonism and its association with the pattern of codon usages.

bioinformatics↗

bioRxiv2022

Structural characterizations of a unusual peptide CORO1C-47aa encoded by circRNA hsa-circ-0000437 associated with endometrial cancer

Circular RNAs, which have covalently closed ends, is a special type of non-coding RNAs. Recent studies reveal that they are associated with various biochemical pathways. One such involvements of circular RNAs is in the onset of different types of cancers. Though the circular RNAs are known as non-coding RNAs, however, some of them are found to possess the capacities to code for proteins. One such circular RNA is hsa-circ-0000437 which is known to code for a short peptide referred to as CORO1C-47aa. The peptide has anti-angiogenic activity and are associated with the prevention of endometrial cancer. However, till date only the amino acid sequence of the peptide is known and no structural details of the peptide are available. Therefore, in this work, our aim was to predict how the peptide would fold and what could be its possible ligand binding sites. We used computational tools to determine the structure of the peptide. The structure was refined by molecular dynamics simulations. The possible binding sites and the binding partners of the peptide were also predicted. From this structure function analysis study, we tried to elucidate the possible mechanism of the involvements of the peptide in the onset of endometrial cancer. This is the first report on the structural characterization of the peptide. This study may therefore be useful in determining the structures of new drug candidates for the treatment of endometrial cancer.

bioinformatics↗

bioRxiv2022

A fast yet force-effective mode of collective cell migration on aligned fibers due to rapid stabilization of contractile forces

Cell collectives, like other motile entities, generate and use forces to move forward. Here, we ask whether environmental configurations alter this proportional force-speed relationship, since aligned extracellular matrix fibers are known to cause directed migration. We show that aligned fibers serve as active conduits for spatial propagation of cellular mechanotransduction through matrix exoskeleton, leading to efficient directed collective cell migration. Epithelial (MCF10A) cell clusters adhered to soft substrates with aligned collagen fibers (AF) migrate faster with much lesser traction forces, compared to random fibers (RF). Fiber alignment causes higher motility waves and transmission of normal stresses deeper into cell monolayer while minimizing shear stresses and increased cell-division based fluidization. By contrast, fiber randomization induces cellular jamming due to breakage in motility waves, disrupted transmission of normal stresses, and heightened shear driven flow. Using a novel motor-clutch model, we explain that such force-effective fast migration phenotype occurs due to rapid stabilization of contractile forces at the migrating front, enabled by higher frictional forces arising from simultaneous compressive loading of parallel fiber-substrate connections. We also model haptotaxis to show that increasing ligand connectivity (but not continuity) increases migration efficiency. According to our model, increased rate of front stabilization via higher resistance to substrate deformation is sufficient to capture durotaxis. Thus, our findings reveal a new paradigm wherein the rate of leading-edge stabilization determines the efficiency of supracellular collective cell migration.

biophysics↗

bioRxiv2022

In vivo functional genomics identifies essentiality of potassium homeostasis in medulloblastoma

The identification of cancer maintenance genes--driver genes essential to tumor survival--is fundamental for developing effective cancer therapy. Transposon-based insertional mutagenesis screens can identify cancer driver genes broadly but not discriminate maintenance from progression or initiation drivers, which contribute to cancer phenotypes and tumorigenesis, respectively. We engineered a nested, double-jumping transposon system to first dysregulate gene expression during tumorigenesis and then restore gene expression following tumor induction, allowing for genome-wide screening of maintenance essentiality in vivo. In a mouse model of medulloblastoma, the most common pediatric malignancy, insertion and remobilization of this nested transposon uncovers potassium channel genes as recurrent maintenance drivers. In human medulloblastoma, KCNB2 is the most overexpressed potassium channel across Group 3, Group 4, and SHH subgroups, and Kcnb2 knockout in mice diminishes the replicative potential of medulloblastoma-propagating cells to mitigate tumor growth. Kcnb2 governs potassium homeostasis to regulate plasma membrane tension-gated EGFR signaling, which drives proliferative expansion of medulloblastoma-propagating cells. Thus, our novel transposon system reveals potassium homeostasis as essential to tumor maintenance through biomechanical modulation of membrane signaling.

cancer biology↗

bioRxiv2022

Editing the core region in HPFH deletions alters fetal and adult globin expression for treatment of β-hemoglobinopathies

Reactivation of fetal hemoglobin (HbF) is the commonly adapted strategy to ameliorate {beta}-hemoglobinopathies. However, the continued production of defective adult hemoglobin (HbA) limits the HbF tetramer production affecting the therapeutic benefits. Here, we tested various deletional hereditary persistence of fetal hemoglobin (HPFH) mutations and identified a 11 kb sequence, encompassing Putative Repressor Region (PRR) to {beta}-globin Exon-1 ({beta}E1), as the core deletion that ablates HbA and exhibit superior production of HbF compared to HPFH or other well-established targets. The PRR-{beta}E1 edited hematopoietic stem and progenitor cells (HSPCs) retained engraftment potential to repopulate for long-term hematopoiesis in immunocompromised mice generating HbF+ cells in vivo. Importantly, the editing induces therapeutically relevant levels of HbF to reverse the phenotypes of both sickle cell disease and {beta}-thalassemia major. These results indicate that the PRR-{beta}E1 gene editing in patient HSPCs can potentially lead to superior therapeutic outcomes for {beta}-hemoglobinopathies gene therapy.

biochemistry↗

bioRxiv2022

Enhancement of mitochondrial function fosters B cell immune memory

Differentiation of T and B cells to effector and memory cell fates are associated with extensive metabolic changes which are accompanied by altered mitochondrial dynamics. However, whether alterations in mitochondrial structure and function plays an active role in regulating effector versus memory cell fate decisions during immune responses remains unclear. Our studies here characterize changes in mitochondrial dynamics in activated B cells and show that increased mitochondrial mass and activity is a distinct feature of memory B cell lineage commitment in vivo. Using a directed screen of mitochondrial modulators, we identify mitochondrial fission inhibitor, Mdivi-1 as an agent that could enhance mitochondrial mass and function leading to augmented memory B cell differentiation. The enhanced memory B cell responses mediated by Mdivi-1, translated to more robust recall responses upon secondary antigen exposures. Moreover, Mdivi-1 when used in combination with subunit (SARS-CoV2) and inactivated (H1N1 influenza) vaccines led to remarkably improved vaccine efficacies and protection from lethal viral (H1N1) challenge. Single-cell transcriptomics revealed enhanced commitment to memory lineage differentiation in B cells following Mdivi-1 treatment. We propose that mitochondrial modulators such as Mdivi-1 are a novel class of "immune enhancers" that specifically reinforces immunological memory and could be broadly applied to improve the fidelity of immune responses and vaccine efficacies.

immunology↗

bioRxiv2020

A JAK/STAT-Mediated Inflammatory Signaling Cascade Drives Oncogenesis In AF10-Rearranged AML

Leukemias bearing fusions of the AF10/MLLT10 gene are associated with poor prognosis, and therapies targeting these fusion proteins are lacking. To understand mechanisms underlying AF10 fusion-mediated leukemogenesis, we generated inducible mouse models of AML driven by the most common AF10 fusion proteins, PICALM/CALM-AF10 and KMT2A/MLL-AF10, and performed comprehensive characterization of the disease using transcriptomic, epigenomic, proteomic, and functional genomic approaches. Our studies provide a comprehensive map of gene networks and protein interactors associated with key AF10 fusions involved in leukemia. Specifically, we report that AF10 fusions activate a cascade of JAK/STAT-mediated inflammatory signaling through direct recruitment of JAK1 kinase. Inhibition of the JAK/STAT signaling by genetic Jak1 deletion or through pharmacological JAK/STAT inhibition elicited potent anti-oncogenic effects in mouse and human models of AF10 fusion AML. Collectively, our study identifies JAK1 as a tractable therapeutic target in AF10-rearranged leukemias. STATEMENT OF SIGNIFICANCEGene fusions of AF10/MLLT10 are recurrent in acute myeloid and lymphoid leukemia and are associated with extremely poor survival outcomes. We show that the JAK1 kinase is required for activation of the AF10 fusion oncotranscriptome and for leukemogenesis. Since a number of JAK/STAT pathways inhibitors are in clinical development or approved for use, our studies may help develop a therapeutic strategy for AF10-rearranged leukemias.

cancer biology↗