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Supplementary Figure S1. Leukocyte frequencies in breast tissues. Supplementary Figure S2. Genes expressed in T cells. Supplementary Figure S3. Activity status of T cells. Supplementary Figure S4. TCR clonotypes in breast tissues. Supplementary Figure S5. Functional state of T cells. Supplementary Figure S6. Tumor topology. Supplementary Figure S7. Immune-related amplicons in breast cancer.

Supplementary Table S1. List of tissue samples used. Supplementary Table S2. Raw FACS data in each sample. Supplementary Table S3. List of differentially expressed genes. Supplementary Table S4. Results of GSEA analyses. Supplementary Table S5. Gene lists used for functional analyses. Supplementary Table S6. Statistical modeling of ERBB2 and CC co-amplification; and PDL1 amplification. Supplementary Table S7. ERBB2 and 17q12 FISH data. Supplementary Table S8. List of antibodies used.

Supplementary Figure 1. Pro-inflammatory cytokines are elevated in MF mice and reversed with JAK inhibitor treatment. Supplementary Figure 2. Principal component analysis of MF cells. Supplementary Figure 3. Single cell analysis of immunophenotypically-defined subpopulations from MF and control mice. Supplementary Figure 4. Elevated IL8 expression in MF patients. Supplementary Figure 5. Complete removal of Il6 from the mouse system shows only minor effects on MPLW515L disease. Supplementary Figure 6. Peripheral blood and cytometric flow analysis of MPLW515L transplanted mice with and without Stat3 deletion. Supplementary Figure 7. Constitutive activation of STAT3 in the BM of MPLW515L mice and primary MF patients. Supplementary Figure 8. Schematic illustration of bone marrow transplantation experiments using Stat3-deficient mice or littermate control mice as donors. Supplementary Figure 9. Excision of Stat3 post engraftment prolongs survival and reduces leukocytosis. Supplementary Figure 10. Mutant-restricted deletion of Stat3 does not affect disease severity in vivo. Supplementary Figure 11. Single cell analysis of populations from MF and control mice. Supplementary Figure 12. Mutant and non-mutant hematopoietic cells feature a higher percentage of cytokine secreting cells. Supplementary Figure 13. Single cell analysis of populations from Jak2V617F MF and control mice. Supplementary Figure 14. Mutant and non-mutant hematopoietic cells feature a higher percentage of cytokine secreting cells. Supplementary Figure 15. JAK1/2 inhibition reduces cytokine expression from CD45.1-positive wild-type cells and CD45.2-positive mutant cell population. Supplementary Table 1. Primary myelofibrosis patient characteristics. Supplementary Table 2. Genetic alterations of patient PMF#11.

Adherens junctions (AJs) create spatially and mechanically discrete microdomains at the interfaces of cells. Using a mechanogenetic platform that generates artificial AJs with controlled protein localization, clustering, and mechanical loading, we report that AJs also organize proteolytic hotspots for γ-secretase with a spatially-regulated substrate selectivity that is critical in the processing of Notch and other transmembrane proteins. Membrane microdomains outside of AJs exclusively organize Notch ligand-receptor engagement (LRE-µdomain) to initialize receptor activation. Conversely, membrane microdomains within AJs exclusively serve to coordinate regulated intramembrane proteolysis (RIP-µdomain). They do so by concentrating γ-secretase and primed receptors while excluding full-length Notch. AJs induce these functionally distinct microdomains by means of cholesterol-dependent γ-secretase recruitment and size-dependent protein segregation. By excluding full-length Notch from RIP-µdomains, AJs prevents inappropriate enzyme-substrate interactions and suppresses spurious Notch activation. Ligand-induced ectodomain shedding eliminates size-dependent segregation, releasing Notch to translocate into AJs for processing by γ-secretase. This mechanism directs radial differentiative expansion of ventricular zone-neural progenitor cells in vivo and more broadly regulates the proteolysis of large cell-surface receptors like amyloid precursor protein. These findings suggest an unprecedented role of AJs in creating size-selective spatial switches that choreograph γ-secretase processing of multiple transmembrane proteins regulating development, homeostasis, and disease.

Most human tumours are heterogeneous, composed of cellular clones with different properties present at variable frequencies. Highly heterogeneous tumours have poor clinical outcomes, yet the underlying mechanism remains poorly understood. Here, we show that minor subclones of breast cancer cells expressing IL11 and FIGF (VEGFD) cooperate to promote metastatic progression and generate polyclonal metastases composed of driver and neutral subclones. Expression profiling of the epithelial and stromal compartments of monoclonal and polyclonal primary and metastatic lesions revealed that this cooperation is indirect, mediated through the local and systemic microenvironments. We identified neutrophils as a leukocyte population stimulated by the IL11-expressing minor subclone and showed that the depletion of neutrophils prevents metastatic outgrowth. Single-cell RNA-seq of CD45+ cell populations from primary tumours, blood and lungs demonstrated that IL11 acts on bone-marrow-derived mesenchymal stromal cells, which induce pro-tumorigenic and pro-metastatic neutrophils. Our results indicate key roles for non-cell-autonomous drivers and minor subclones in metastasis.

Multifunctional magnetic nanoparticles have shown great promise as next-generation imaging and perturbation probes for deciphering molecular and cellular processes. As a consequence of multicomponent integration into a single nanosystem, pre-existing nanoprobes are typically large and show limited access to biological targets present in a crowded microenvironment. Here, we apply organic-phase surface PEGylation, click chemistry, and charge-based valency discrimination principles to develop compact, modular, and monovalent magnetofluorescent nanoparticles (MFNs). We show that MFNs exhibit highly efficient labeling to target receptors present in cells with a dense and thick glycocalyx layer. We use these MFNs to interrogate the E-cadherin-mediated adherens junction formation and F-actin polymerization in a three-dimensional space, demonstrating the utility as modular and versatile mechanogenetic probes in the most demanding single-cell perturbation applications.

To cope with the negative oil futures price caused by the COVID-19 recession, global commodity futures exchanges temporarily switched the option model from Black--Scholes to Bachelier in 2020. This study reviews the literature on Bachelier's pioneering option pricing model and summarizes the practical results on volatility conversion, risk management, stochastic volatility, and barrier options pricing to facilitate the model transition. In particular, using the displaced Black-Scholes model as a model family with the Black-Scholes and Bachelier models as special cases, we not only connect the two models but also present a continuous spectrum of model choices.

Aberrant cleavage of Notch by γ-secretase is implicated in numerous diseases, but how cleavage is regulated in space and time is unclear. Here, we report that cadherin-based adherens junctions (cadAJs) are sites of high cell-surface γ-secretase activity, as well as sites of constrained physical space that excludes γ-secretase substrates having large extracellular domains (ECDs) like Notch. ECD shedding initiates drastic spatial relocalization of Notch to cadAJs, allowing enzyme-substrate interactions and downstream signaling. Spatial mutations by adjusting the ECD size or the physical constraint alter signaling. Dysregulation of this spatial switch promotes precocious differentiation of ventricular zone neural progenitor cells in vivo. We show the generality of this spatial switch for amyloid precursor protein proteolysis. Thus, cadAJs create spatially distinct biochemical compartments regulating cleavage events involving γ-secretase and preventing aberrant activation of receptors.

To investigate immune escape during breast tumor progression, we analyzed the composition of leukocytes in normal breast tissues, ductal carcinoma in situ (DCIS), and invasive ductal carcinomas (IDC). We found significant tissue and tumor subtype-specific differences in multiple cell types including T cells and neutrophils. Gene expression profiling of CD45+CD3+ T cells demonstrated a decrease in CD8+ signatures in IDCs. Immunofluorescence analysis showed fewer activated GZMB+CD8+ T cells in IDC than in DCIS, including in matched DCIS and recurrent IDC. T-cell receptor clonotype diversity was significantly higher in DCIS than in IDCs. Immune checkpoint protein TIGIT-expressing T cells were more frequent in DCIS, whereas high PD-L1 expression and amplification of CD274 (encoding PD-L1) was only detected in triple-negative IDCs. Coamplification of a 17q12 chemokine cluster with ERBB2 subdivided HER2+ breast tumors into immunologically and clinically distinct subtypes. Our results show coevolution of cancer cells and the immune microenvironment during tumor progression. Significance: The design of effective cancer immunotherapies requires the understanding of mechanisms underlying immune escape during tumor progression. Here we demonstrate a switch to a less active tumor immune environment during the in situ to invasive breast carcinoma transition, and identify immune regulators and genomic alterations that shape tumor evolution. Cancer Discov; 7(10); 1098–115. ©2017 AACR. See related commentary by Speiser and Verdeil, p. 1062. This article is highlighted in the In This Issue feature, p. 1047

Following uncontrolled proliferation, a subset of primary tumour cells acquires additional traits/mutations to trigger phenotypic changes that enhance migration and are hypothesized to be the initiators of metastasis. This study reveals an adaptive mechanism that harnesses synergistic paracrine signalling via IL-6/8, which is amplified by cell proliferation and cell density, to directly promote cell migration. This effect occurs in metastatic human sarcoma and carcinoma cells– but not in normal or non-metastatic cancer cells-, and likely involves the downstream signalling of WASF3 and Arp2/3. The transcriptional phenotype of high-density cells that emerges due to proliferation resembles that of low-density cells treated with a combination of IL-6/8. Simultaneous inhibition of IL-6/8 receptors decreases the expression of WASF3 and Arp2/3 in a mouse xenograft model and reduces metastasis. This study reveals a potential mechanism that promotes tumour cell migration and infers a strategy to decrease metastatic capacity of tumour cells., Tumor cell proliferation and migration, key drivers of metastasis, can be mechanistically coupled in matrix embedded human sarcoma and carcinoma cells through cell density via a synergistic, paracrine signaling mechanism between Interleukins 6/8. Inhibition of this mechanism significantly decreases metastasis in mouse xenograft models.

Co-measurement of multiple omic profiles from the same single cells opens up the opportunity to decode molecular regulation that underlie intercellular heterogeneity in development and disease. Here, we present co-sequencing of microRNAs and mRNAs in the same single cells using a half-cell genomics approach. This method demonstrates good robustness (~95% success rate) and reproducibility (R2=0.93 for both miRNAs and mRNAs), and yields paired half-cell miRNA and mRNA profiles that could be independently validated. Linking the level of miRNAs to the expression of predicted target mRNAs across 19 single cells that are phenotypically identical, we observe that the predicted targets are significantly anti-correlated with the variation of abundantly expressed miRNAs, suggesting that miRNA expression variability alone may lead to non-genetic cell-to-cell heterogeneity. Genome-scale analysis of paired miRNA-mRNA co-profiles further allows us to derive and validate new regulatory relationships of cellular pathways controlling miRNA expression and variability.

We examine how the bequest motive and the incentive affect the consumption, investment, life insurance, and retirement decision of a wage earner with uncertain lifetime. We find, unlike the fixed retirement time model, risky investment prior to retirement decreases as the bequest motive becomes stronger or as the incentive to retire weaker, even though the retirement wealth threshold increases.

Inorganic nanowires are among the most attractive functional materials, which have emerged in the past two decades. They have demonstrated applications in information technology and energy conversion, but their utility in biological or biomedical research remains relatively under-explored. Although nanowire-based sensors have been frequently reported for biomolecular detection, interfacing nanowire arrays and living mammalian cells for the direct analysis of cellular functions is a very recent endeavor. Cell-penetrating nanowires enabled effective delivery of biomolecules, electrical and optical stimulation and recording of intracellular signals over a long period of time. Non-penetrating, high-density nanowire arrays display rich interactions between the nanostructured substrate and the micro/nanoscale features of cell surfaces. Such interactions enable efficient capture of rare cells including circulating tumor cells and trafficking leukocytes from complex biospecimens. It also serves as a platform for probing cell traction force and neuronal guidance. The most recent advances in the field that exploits nanowire arrays (both penetrating and non-penetrating) to perform rapid analysis of cellular functions potentially for disease diagnosis and monitoring are reviewed.

The identification of JAK2/MPL mutations in patients with myeloproliferative neoplasms (MPN) has led to the clinical development of JAK kinase inhibitors, including ruxolitinib. Ruxolitinib reduces splenomegaly and systemic symptoms in myelofibrosis and improves overall survival; however, the mechanism by which JAK inhibitors achieve efficacy has not been delineated. Patients with MPN present with increased levels of circulating proinflammatory cytokines, which are mitigated by JAK inhibitor therapy. We sought to elucidate mechanisms by which JAK inhibitors attenuate cytokine-mediated pathophysiology. Single-cell profiling demonstrated that hematopoietic cells from myelofibrosis models and patient samples aberrantly secrete inflammatory cytokines. Pan-hematopoietic Stat3 deletion reduced disease severity and attenuated cytokine secretion, with similar efficacy as observed with ruxolitinib therapy. In contrast, Stat3 deletion restricted to MPN cells did not reduce disease severity or cytokine production. Consistent with these observations, we found that malignant and nonmalignant cells aberrantly secrete cytokines and JAK inhibition reduces cytokine production from both populations. Significance: Our results demonstrate that JAK–STAT3-mediated cytokine production from malignant and nonmalignant cells contributes to MPN pathogenesis and that JAK inhibition in both populations is required for therapeutic efficacy. These findings provide novel insight into the mechanisms by which JAK kinase inhibition achieves therapeutic efficacy in MPNs. Cancer Discov; 5(3); 316–31. ©2015 AACR. See related commentary by Belver and Ferrando, p. 234 This article is highlighted in the In This Issue feature, p. 213

We report a Mg alloy Mg-2.2Nd-0.1Zn-0.4Zr (wt.%, denoted as JDBM-2) showing great potential in clinical vascular stent application by integrating the advantages of traditional medical stainless steel and polymer. This alloy exhibits high yield strength and elongation of 276 ± 6 MPa and 34.3 ± 3.4% respectively. The JDBM-2 with a stable degradation surface results in a highly homogeneous degradation mechanism and long-term structural and mechanical durability. In vitro cytotoxicity test of the Mg extract via human vascular endothelial cells (HUVECs) indicates that the corrosion products are well tolerated by the tested cells and potentially negligible toxic effect on arterial vessel walls. This alloy also exhibits compromised foreign body response (FBR) determined by human peripheral blood derived macrophage adhesion, foreign body giant cell (FBGC) formation and inflammatory cytokine and chemokine secretion. Finally, vascular stents manufactured from the JDBM-2 were implanted into rabbits for long-term evaluation. The results confirm excellent tissue compatibility and up to 6-month structural and mechanical integrity of the stent in vivo. Thus, the JDBM-2 stent with up to 6-month structural and mechanical integrity and excellent tissue compatibility represents a major breakthrough in this field and a promising alternative to traditional medical stainless steel and polymer for the clinical application.

We report on the rapid and direct quantification of specific cell captures using a micro-patterned streptavidin (STR)-functionalized silicon nanowire (SiNW) platform, which was prepared by Ag-assisted wet chemical etching and a photo-lithography process. This platform operates by high-affinity cell capture rendered by the combination of antibody-epithelial cell surface-binding, biotin-streptavidin binding, and the topologically enhanced cell-substrate interaction on a 3-dimensional SiNWs array. In this work, we developed a micro-patterned nanowire platform, with which we were able to directly evaluate the performance enhancement due to nanotopography. An excellent capture efficiency of ~96.6±6.7%, which is the highest value achieved thus far for the targeting specific A549 cells on a selective area of patterned SiNWs, is demonstrated. Direct comparison between the nanowire region and the planar region on the same substrate indicates dramatically elevated cell-capture efficiency on nanotopological surface identical surface chemistry (

We study an optimal portfolio and consumption choice problem of a family that combines life insurance for parents who receive deterministic labor income until the fixed time T . We consider utility functions of parents and children separately and assume that parents have an uncertain lifetime. If parents die before time T , children have no labor income and they choose the optimal consumption and portfolio with remaining wealth and life insurance benefit. The object of the family is to maximize the weighted average of utility of parents and that of children. We obtain analytic solutions for the value function and the optimal policies, and then analyze how the changes of the weight of the parents’ utility function and other factors affect the optimal policies.

Most breast tumors display a high degree of intratumor heterogeneity, with many distinct subpopulations of cancer cells present. Elevated diversity within a tumor increases the chance for cellular adaptation, as individual clones may react differently to changes in the tumor microenvironment. Thus, treatment of heterogeneous tumors my lead to selection of a resistant clone, its expansion, and tumor progression. However, the fitness of cancer cells depends not only on their intrinsic properties, but could also be affected through interactions between different subpopulations. These interactions could be the reason for maintenance of minor clones along the major population. Therefore, intratumor heterogeneity may have functional relevance in tumor progression and colonization of metastatic sites. To emulate clonal interactions, we used the previously developed polyclonal breast cancer model of MDA-MB-468 cell line expressing soluble factors, IL-11 and FIGF. The IL-11 and FIGF clones, when present as minor population, support the growth of other clones in vivo. Moreover, polyclonal tumors with minor driving clone population are highly metastatic. Thus, we hypothesized that clonal interactions could not only drive tumor growth, but could also play an important role in metastasis. We have found that polyclonal tumors lead to polyclonal metastases, composed of mixture of neutral and driver clones. To investigate the mechanisms of clonal interactions driving polyclonal metastasis, we performed RNA profiling of subpopulations and stroma from polyclonal tumors. Our results suggest that this cooperation is indirect and that driver clones promote metastasis by altering the tumor microenvironment. We have also found that minor driver clones affect the immune cells within primary tumor, circulating blood, and metastatic site. These systemic changes significantly influence the metastatic progression. We are currently testing whether a treatment targeting this indirect clonal interaction mechanism could prevent polyclonal metastatic spread. Our study shows that the interaction between minor clones and other cancer cells could drive tumor growth and metastasis. Moreover, our results suggest that clonal cooperation in metastatic progression may be indirect and involve modulation of immune microenvironment of the primary tumor and distant organs. This abstract is also being presented as Poster B03. Citation Format: Michalina Janiszewska, Doris P. Tabassum, Andriy Marusyk, Muhammad B. Ekram, Zafira Castaño, Natalie L. Kingston, Yuanbo Qin, Tyler Laszewski, Minsuk Kwak, Kimiyo Nakamura, Rong Fan, Franziska Michor, Sandra S. McAllister, Kornelia Polyak. Minor clones can drive polyclonal metastasis by affecting immune microenvironment [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr PR02.

We investigate an optimal portfolio, consumption and retirement decision problem in which an economic agent can determine the discretionary stopping time as a retirement time with constant labor wage and disutility. We allow the preference of the agent to be changed before and after retirement. It is assumed that the agent's coefficient of relative risk aversion becomes higher after retirement. Under a constant relative risk aversion (CRRA) utility function, we obtain the optimal policies in closed-forms using martingale methods and variational inequality methods. We give some numerical results of the optimal policies. We also consider the relation between the level of disutility and the labor wage with the optimal retirement wealth level.

Despite the presence of the blood–brain barrier (BBB) that restricts the entry of immune cells and mediators into the central nervous system (CNS), a small number of peripheral leukocytes can traverse the BBB and infiltrate into the CNS. The cerebrospinal fluid (CSF) is one of the major routes through which trafficking leukocytes migrate into the CNS. Therefore, the number of leukocytes and their phenotypic compositions in the CSF may represent important sources to investigate immune-to-brain interactions or diagnose and monitor neurodegenerative diseases. Due to the paucity of trafficking leucocytes in the CSF, a technology capable of efficient isolation, enumeration, and molecular typing of these cells in the clinical settings has not been achieved. In this study, we report on a biofunctionalized silicon nanowire array chip for highly efficient capture and multiplexed phenotyping of rare trafficking leukocytes in small quantities (50 microliters) of clinical CSF specimens collected from neurodegenerative disease patients. The antibody coated 3D nanostructured materials exhibited vastly improved rare cell capture efficiency due to high-affinity binding and enhanced cell–substrate interactions. Moreover, our platform creates multiple cell capture interfaces, each of which can selectively isolate specific leukocyte phenotypes. A comparison with the traditional immunophenotyping using flow cytometry demonstrated that our novel silicon nanowire-based rare cell analysis platform can perform rapid detection and simultaneous molecular characterization of heterogeneous immune cells. Multiplexed molecular typing of rare leukocytes in CSF samples collected from Alzheimer's disease patients revealed the elevation of white blood cell counts and significant alterations in the distribution of major leukocyte phenotypes. Our technology represents a practical tool for potentially diagnosing and monitoring the pathogenesis of neurodegenerative diseases by allowing an effective hematological analysis of the CSF from patients.

We propose an equilibrium pricing model in a dynamic multiperiod stochastic framework with uncertain income. There are one tradable risky asset (stock/commodity), one nontradable underlying (temperature), and also a contingent claim (weather derivative) written on the tradable risky asset and the nontradable underlying in the market. The price of the contingent claim is priced in equilibrium by optimal strategies of representative agent and market clearing condition. The risk preferences are of exponential type with a stochastic coefficient of risk aversion. Both subgame perfect strategy and naive strategy are considered and the corresponding equilibrium prices are derived. From the numerical result we examine how the equilibrium prices vary in response to changes in model parameters and highlight the importance of our equilibrium pricing principle.

In this paper, we propose an equilibrium pricing model in a dynamic multi-period stochastic framework with uncertain income. There are one tradable risky asset (stock/commodity), one non-tradable underlying (temperature), and also a contingent claim (weather derivative) written on the tradable risky asset and the non-tradable underlying in the market. The price of the contingent claim is priced in equilibrium by optimal strategies of representative agent and market clearing condition. The risk preferences are of exponential (CARA) type with a stochastic coefficient of risk aversion. Both Nash subgame perfect strategies and naive strategies are considered. From the numerical result we examine how the equilibrium prices vary in response to changes in model parameters and highlight the importance of Nash equilibrium pricing principle.

We report on the development of a nanowire substrate-enabled laser scanning imaging cytometry for rare cell analysis in order to achieve quantitative, automated, and functional evaluation of circulating tumor cells. Immuno-functionalized nanowire arrays have been demonstrated as a superior material to capture rare cells from heterogeneous cell populations. The laser scanning cytometry method enables large-area, automated quantitation of captured cells and rapid evaluation of functional cellular parameters (e.g. size, shape and signaling protein) at the single-cell level. This integrated platform was first tested for capture and quantitation of human lung carcinoma cells from a mixture of tumor cells and leukocytes. We further applied it to the analysis of rare tumor cells spiked in fresh human whole blood (several cells per mL) that emulate metastatic cancer patient blood and demonstrated the potential of this technology for analyzing circulating tumor cells in the clinical settings. Using a high-content image analysis algorithm, cellular morphometric parameters and fluorescence intensities can be rapidly quantitated in an automated, unbiased, and standardized manner. Together, this approach enables informative characterization of captured cells in situ and potentially allows for sub-classification of circulating tumor cells, a key step towards the identification of true metastasis-initiating cells. Thus, this nano-enabled platform holds great potential for studying the biology of rare tumor cells and for differential diagnosis of cancer progression and metastasis.

The discovery of JAK2/MPL mutations in the majority of patients with Myeloproliferative Neoplasms (MPN) led to the development of JAK kinase inhibitors. JAK kinase inhibitors, including ruxolitinib, improve patient constitutional symptoms and reduce splenomegaly, but do not significantly reduce mutant allele burden. Chronic exposure to JAK kinase inhibitors results in JAK inhibitor persistence in cell lines, murine models, and patient samples, which we have shown is due to JAK2-transactivation and persistent JAK-STAT signaling. We have used murine genetic studies show that MPN cells remain dependent on JAK2 expression for proliferation and survival. These data suggest that pharmacologic approaches that better inhibit JAK2 activity in MPN cells may demonstrate increased efficacy in vivo. All JAK inhibitors in clinical development are type I inhibitors that interact with and inhibit the active confirmation of the JAK2 kinase. We hypothesized that novel, type II JAK inhibitors that interact with and inhibit JAK2 in the inactive conformation might retain activity in JAK inhibitor persistent cells and show increased efficacy in murine MPN models. Signaling studies demonstrated that CHZ868 more potently attenuated JAK-STAT signaling in JAK2/MPL-mutant cells, with suppression of JAK2 phosphorylation consistent with a type II mechanism of kinase inhibition. CHZ868 completely suppressed JAK-STAT signaling in type I JAK inhibitor-persistent cells, and prevented heterodimeric activation of JAK2 by JAK1 and TYK2. Most importantly, JAK2/MPL-mutant cells which were insensitive to type I JAK inhibitors remained highly sensitive to CHZ868, demonstrating that type I JAK inhibitor persistence does not confer resistance to type II inhibitors. CHZ868 showed significant activity in murine models of Jak2V617F-induced polycythemia vera, and MPLW515L-mutant MF, with normalization of blood counts, stem/progenitor expansion, spleen weights, and extramedullary hematopoiesis in vivo. Most importantly, CHZ868 resulted in significant reductions of mutant allele burden in these models. In addition, it has not been delineated whether the clinical benefits of JAK inhibitors are solely from target inhibition in MPN cells, or if JAK-STAT inhibition in malignant and non-malignant cells contributes to the therapeutic response. We show that the levels of circulating cytokines are elevated in MF and that cytokine production is reduced with JAK inhibitor treatment. Importantly, aberrant cytokine production in MF emanates from both malignant and non-malignant cells, and that JAK inhibition reduces cytokine production from both tumor and non-tumor populations. Our data suggest inhibition of JAK-STAT signaling in malignant and non-malignant cells is required to improve symptoms, reduce disease severity, and to reduce disease progression. Moreover, optimizing therapies to potently inhibit JAK-STAT signaling in malignant and non-malignant cells are warranted to improve clinical efficacy and outcomes in MPN patients. Citation Format: Sara Meyer, Maria Kleppe, Neha Bhagwat, Priya Koppikar, Minsuk Kwak, Thomas Radimerski, Rong Fan, Ross L. Levine. Role of JAK-STAT pathway activation in MPN pathogenesis and therapeutic response. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr IA41.