JAK2/IDH-mutant–driven myeloproliferative neoplasm is sensitive to combined targeted inhibition

Patients with myeloproliferative neoplasms (MPNs) frequently progress to bone marrow failure or acute myeloid leukemia (AML), and mutations in epigenetic regulators such as the metabolic enzyme isocitrate dehydrogenase (IDH) are associated with poor outcomes. Here, we showed that combined expression of Jak2V617Fand mutant IDH1R132Hor Idh2R140Q induces MPN progression, alters stem/progenitor cell function, and impairs differentiation in mice. Jak2V617FIdh2R140Q–mutant MPNs were sensitive to small-molecule inhibition of IDH. Combined inhibition of JAK2 and IDH2 normalized the stem and progenitor cell compartments in the murine model and reduced disease burden to a greater extent than was seen with JAK inhibition alone. In addition, combined JAK2 and IDH2 inhibitor treatment also reversed aberrant gene expression in MPN stem cells and reversed the metabolite perturbations induced by concurrent JAK2 and IDH2 mutations. Combined JAK2 and IDH2 inhibitor therapy also showed cooperative efficacy in cells from MPN patients with both JAK2mutand IDH2mutmutations. Taken together, these data suggest that combined JAK and IDH inhibition May offer a therapeutic advantage in this high-risk MPN subtype.Damon Runyon Cancer Research Foundation (DRG-2241-15)Howard Hughes Medical Institute (Faculty Scholars Award)Stand Up To CancerNational Cancer Institute (U.S.) (P50CA165962)National Cancer Institute (U.S.) (P30CA14051)Koch Institute for Integrative Cancer Research ( Dana-Farber Harvard Cancer Center Bridge Project)Leukemia & Lymphoma Society of America. Specialized Center of Research (SCOR) ProgramNational Institutes of Health (U.S.) (grant U54OD020355-01)National Institutes of Health (U.S.) (grant NCI R01CA172636)National Institutes of Health (U.S.) (grant R35CA197594)National Cancer Institute (U.S.) (Cancer Center Support Grant (P30 CA008747)

Role of neoplastic monocyte-derived fibrocytes in primary myelofibrosis

Primary myelofibrosis (PMF) is a fatal neoplastic disease characterized by clonal myeloproliferation and progressive bone marrow (BM) fibrosis thought to be induced by mesenchymal stromal cells stimulated by overproduced growth factors. However, tissue fibrosis in other diseases is associated with monocyte-derived fibrocytes. Therefore, we sought to determine whether fibrocytes play a role in the induction of BM fibrosis in PMF. In this study, we show that BM from patients with PMF harbors an abundance of clonal, neoplastic collagen- and fibronectin-producing fibrocytes. Immunodeficient mice transplanted with myelofibrosis patients’ BM cells developed a lethal myelofibrosis-like phenotype. Treatment of the xenograft mice with the fibrocyte inhibitor serum amyloid P (SAP; pentraxin-2) significantly prolonged survival and slowed the development of BM fibrosis. Collectively, our data suggest that neoplastic fibrocytes contribute to the induction of BM fibrosis in PMF, and inhibiting fibrocyte differentiation with SAP may interfere with this process

Characterization of [1]Benzothieno[3,2-<i>b</i>]benzothiophene (BTBT) Derivatives with End-Capping Groups as Solution-Processable Organic Semiconductors for Organic Field-Effect Transistors

Solution-processable [1]benzothieno[3,2-b]benzothiophene (BTBT) derivatives with various end-capping groups, 2-(phenylethynyl)benzo[b]benzo[4,5]thieno[2,3-d]thiophene (Compound 1), 2-octyl-7-(5-(phenylethynyl)thiophen-2-yl)benzo[b]benzo[4,5]thieno[2,3-d]thiophene (Compound 2), and triisopropyl((5-(7-octylbenzo[b]benzo[4,5]thieno[2,3-d]thiophen-2-yl)thiophen-2-yl)ethynyl)silane (Compound 3), have been synthesized and characterized as active layers for organic field-effect transistors (OFETs). Thermal, optical, and electrochemical properties of the newly synthesized compounds were characterized using thermogravimetric analysis (TGA), a differential scanning calorimeter (DSC), UV–vis spectroscopy, and cyclic voltammetry (CV). Thin films of each compound were formed using the solution-shearing method and the thin film surface morphology and texture of the corresponding films were characterized using atomic force microscopy (AFM) and θ–2θ X-ray diffraction (XRD). All semiconductors exhibited p-channel characteristics in ambient and Compound 1 showed the highest electrical performance with a carrier mobility of ~0.03 cm2/Vs and current on/off ratio of ~106

Telomere Length Is Associated with Specific Mutations and Mutation Classes in Patients with Acute Myeloid Leukemia

Abstract It is unknown if telomere length (TL) is associated with clinical outcome or molecular profile in acute myeloid leukemia (AML). We collected tumor samples from 67 AML patients treated at Memorial Sloan Kettering Cancer Center. DNA extraction was performed using viably frozen peripheral blood and bone marrow mononuclear cells. RainDance was used to amplify all exons of a set of 30 genes commonly mutated in AML. Capture was followed by next-generation sequencing; mutations were called if the variant was supported by >5% of the total number of reads (minimum >10 reads). TL was measured as mean telomere content by qPCR. Patients were assessed for FLT3 and NPM1 mutations, cytogenetics, and outcomes by chart review. Results In our 67 patient AML cohort, median TL was 5.22 kb (range 3.73-8.76). Median age was 64.1 years (range 26.2-84.4). While in healthy individuals TL shortens with age, in our cohort there was no association (R2=0.043). There was no difference in TL between newly diagnosed (ND) and relapsed/refractory (RR) patients or between de novo and secondary AML patients. In the 45 ND patients, there was a trend of early improved survival following sample collection in the longest TL tertile compared to the middle and shortest TL tertiles (86.7% vs. 60.0% and 33.3% at 6 months); however, this association was not statistically significant (p=0.662) (Fig 1). In the 22 RR patients, there was also a trend toward improved OS in the longest TL tertile (60.0% vs. 11.1% and 25.0%, p=0.284). In ND patients, there was no association between TL and primary induction failure or relapse-free survival. Targeted sequencing data for 30 myeloid genes were available in 62 of the 67 patients. Analysis of single mutation correlation with TL showed that patients with IDH1 mutations had significantly longer TL than those without (p=0.02) (Table 1). Moreover, mutations in a set of genes associated with epigenetic functions (IDH1/2, ASXL1, DNMT3A, and TET2) also correlated with longer TL when examined together as a group (p=0.073).FLT3-ITD mutations were associated with shorter TL (p=0.084). The median ages of patients with IDH1 or FLT3 mutations were not different from the rest of the cohort. Of note, FLT3-mutated patients did have a higher WBC than FLT3 wild-type patients (p<0.001), suggesting that increased proliferative rate may be associated with shorter TL. Patients with RUNX1 mutations, t(8;21), or inv(16) also had a non-significant trend toward shorter TL (Table 1), and when we examined FLT3, RUNX1, t(8;21), and inv(16) together as a group, there was an association with shorter TL (p=0.026). There was no association between TL and NPM1 mutations. There was no difference in TL in patients with normal (n=35) vs. abnormal karyotype (n=31). Conclusion There was a trend of early improved survival for patients with the longest TL, suggesting that longer TL may be associated with better response rates to chemotherapy. However, the analysis was limited by the relatively small size of our cohort, andlarger studies are needed to further assess this association. We also demonstrated that IDH1 mutations are associated with longer TL (p=0.02), and that TL in general may be associated with specific classes of AML mutations. For example, mutations in transcription factors or receptor tyrosine kinases conferring a proliferative advantage may be associated with shorter TL, while mutations in epigenetic modifiers appear to be associated with longer TL. This is a novel and intriguing finding that warrants further study of TL, mutational profile, and epigenetic alterations in AML. Table 1 Mutation N Median TL (range) p-value IDH1 0.020 negative 56 5.09 (3.73,8.76) positive 6 6.32 (4.81,7.72) IDH2 0.870 negative 59 5.16 (3.73,8.76) positive 3 5.63 (4.10,6.54) DNMT3A 0.697 negative 53 5.08 (3.73,8.76) positive 9 5.53 (4.53,6.29) TET2 0.423 negative 55 5.16 (3.73,7.85) positive 7 5.53 (4.40,8.76) ASXL1 0.219 negative 59 5.10 (3.73,7.85) positive 3 5.56 (5.52,8.76) FLT3-ITD 0.084 negative 46 5.54 (3.95,8.76) positive 12 4.72 (3.97,8.00) RUNX1 0.856 negative 57 5.22 (3.73,8.76) positive 5 4.89 (4.10,6.34) t(8;21) 0.588 negative 64 5.24 (3.73,8.76) positive 2 4.87 (4.81,4.93) inv(16) 0.302 negative 63 5.22 (3.73,8.76) positive 3 4.72 (4.20,5.26) Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare

Telomere length and associations with somatic mutations and clinical outcomes in acute myeloid leukemia

•Telomere length (TL) may be associated with clinical outcomes in AML.•TL in AML appears to be associated with mutational class (i.e. activating vs. epigenetic mutations).•IDH mutations are associated with longer TL. We examined the genetic implications and clinical impact of telomere length (TL) in 67 patients with acute myeloid leukemia (AML). There was a trend toward improved survival at 6 months in patients with longer TL. We found that patients with activating mutations, such as FLT3-ITD, had shorter TL, while those with mutations in epigenetic modifying enzymes, particularly IDH1 and IDH2, had longer TL. These are intriguing findings that warrant further investigation in larger cohorts. Our data show the potential of TL as a predictive biomarker in AML and identify genetic subsets that may be particularly vulnerable to telomere-targeted therapies