As more clinically-relevant genomic features of myeloid malignancies are revealed, it has become clear that targeted clinical genetic testing is inadequate for risk stratification. Here, we develop and validate a clinical transcriptome-based assay for stratification of acute myeloid leukemia (AML). Comparison of ribonucleic acid sequencing (RNA-Seq) to whole genome and exome sequencing reveals that a standalone RNA-Seq assay offers the greatest diagnostic return, enabling identification of expressed gene fusions, single nucleotide and short insertion/deletion variants, and whole-transcriptome expression information. Expression data from 154 AML patients are used to develop a novel AML prognostic score, which is strongly associated with patient outcomes across 620 patients from three independent cohorts, and 42 patients from a prospective cohort. When combined with molecular risk guidelines, the risk score allows for the re-stratification of 22.1 to 25.3% of AML patients from three independent cohorts into correct risk groups. Within the adverse-risk subgroup, we identify a subset of patients characterized by dysregulated integrin signaling and RUNX1 or TP53 mutation. We show that these patients may benefit from therapy with inhibitors of focal adhesion kinase, encoded by PTK2, demonstrating additional utility of transcriptome-based testing for therapy selection in myeloid malignancy.

Introduction: Epstein-Barr virus (EBV) associated smooth muscle tumors (EBV-SMT) are a rare complication of solid organ transplantation (SOT). Incidence data related to this EBV-SMT are limited. EBV DNA is universally present in these tumors. How these cells get infected with EBV, whether this is a result of primary EBV infection vs reactivation, and how persistent active EBV infection post-transplant influences EBV-SMT pathogenesis remains unknown. Methods: Among 5006 SOT recipients (474 pediatric, 4532 adult) receiving SOT at our center between Jan 1984 and Dec 2015, three cases of post-transplant EBV-SMT were identified. Results: All cases were pediatric heart transplants who were EBV seronegative prior to transplant, and experienced primary EBV infection with persistently elevated EBV viral loads, despite antiviral therapy. Two are deceased at 3.2 and 0.9 years post-diagnosis, while one remains alive 6.2 years post diagnosis. The overall local incidence of post-transplant EBV-SMT at our institution was 0.7 (95% CI, 0.2-1.7) per 1000 patient years, and 2.6 (95% CI, 0.6-6.7) per 1000 patient years in pediatric heart transplants. A literature review identified 36 pediatric and 51 adult cases of posttransplant EBV-SMT. Conclusions:We hypothesize that pre-transplant EBV seronegativity, followed by primary EBV infection and persistently high EBV viral loads, represents a unique risk factor for post-transplant EBV-SMT. Pediatric heart transplant recipients were found to be disproportionately affected by post-transplant EBV-SMT at our institution. K E Y W O R D SEBV-associated leiomyosarcoma, EBV-associated smooth muscle tumor, immunodeficiency associated leiomyosarcoma, immunodeficiency associated smooth muscle tumors, posttransplant leiomyosarcoma

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Blocked cellular differentiation is a central pathologic feature of the myeloid malignancies, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Treatment regimens promoting differentiation have resulted in incredible cure rates in certain AML subtypes, such as acute promyelocytic leukemia. Over the past several years, we have seen many new therapies for MDS/AML enter clinical practice, including epigenetic therapies (e.g., 5-azacitidine), isocitrate dehydrogenase (IDH) inhibitors, fms-like kinase 3 (FLT3) inhibitors, and lenalidomide for deletion 5q (del5q) MDS. Despite not being developed with the intent of manipulating differentiation, induction of differentiation is a major mechanism by which several of these novel agents function. In this review, we examine the new therapeutic landscape for these diseases, focusing on the role of hematopoietic differentiation and the impact of inflammation and aging. We review how current therapies in MDS/AML promote differentiation as a part of their therapeutic effect, and the cellular mechanisms by which this occurs. We then outline potential novel avenues to achieve differentiation in the myeloid malignancies for therapeutic purposes. This emerging body of knowledge about the importance of relieving differentiation blockade with anti-neoplastic therapies is important to understand how current novel agents function and may open avenues to developing new treatments that explicitly target cellular differentiation. Moving beyond cytotoxic agents has the potential to open new and unexpected avenues in the treatment of myeloid malignancies, hopefully providing more efficacy with reduced toxicity.