Hepatosplenic T cell lymphoma (HSTL) is a rare and lethal lymphoma; the genetic drivers of this disease are unknown. Through whole exome sequencing of 68 HSTLs, we define recurrently mutated driver genes and copy number alterations in the disease. Chromatin modifying genes including SETD2, INO80 and ARID1B were commonly mutated in HSTL, affecting 62% of cases. HSTLs manifest frequent mutations in STAT5B (31%), STAT3 (9%), and PIK3CD (9%) for which there currently exist potential targeted therapies. In addition, we noted less frequent events in EZH2, KRAS and TP53. SETD2 was the most frequently silenced gene in HSTL. We experimentally demonstrated that SETD2 acts as a tumor suppressor gene. In addition, we found that mutations in STAT5B and PIK3CD activate critical signaling pathways important to cell survival in HSTL. Our work thus defines the genetic landscape of HSTL and implicates novel gene mutations linked to HSTL pathogenesis and potential treatment targets.

Dishevelled (DVL) proteins, three of which have been identified in humans, are highly conserved components of canonical and noncanonical Wnt signaling pathways. These multifunctional proteins, originally discovered in the fruit fly, through their different domains mediate complex signal transduction: DIX (dishevelled, axin) and PDZ (postsynaptic density 95, discs large, zonula occludens-1) domains serve for canonical beta-catenin signaling, while PDZ and DEP (dishevelled, Egl-10, pleckstrin) domains serve for non-canonical signaling. In canonical or beta-catenin signaling, DVL forms large molecular supercomplexes at the plasma membrane consisting of Wnt-Fz-LRP5/6-DVL-AXIN. This promotes the disassembly of the beta-catenin destruction machinery, beta-catenin accumulation, and consequent activation of Wnt signaling. Therefore, DVLs are considered to be key regulators that rescue cytoplasmic beta-catenin from degradation. The potential medical importance of DVLs is in both human degenerative disease and cancer. The overexpression of DVL has been shown to potentiate the activation of Wnt signaling and it is now apparent that up-regulation of DVLs is involved in several types of cancer.

A proportion of patients with multiple myeloma (MM) who have already undergone autologous stem cell transplantation (autoSCT) might benefit from a further transplantation. For this, they might need to undergo another round of stem cell mobilization. We analyzed retrospectively the outcomes of stem cell mobilization with plerixafor and granulocyte colony-stimulating factor (G-CSF) in a group of 30 patients who had undergone autoSCT previously, and in 46 other patients. The previously transplanted patients were significantly different from the remaining patients with respect to the intensity and number of previous therapies. We observed that the median peripheral blood concentration of CD34+ cells after the first administration of plerixafor was lower in previously transplanted (19 cells/μL) than in other patients (30 cells/μL, P < 0.05). Despite a comparable number of apheresis sessions being performed, the median total yield of CD34+ cells was significantly lower in the previously transplanted than in the remaining patients (2.8 × 10(6) cells/kg vs. 4.2 × 10(6) cells/kg, P < 0.05). However, successful collection of at least 2.0 × 10(6) CD34+ cells/kg was achieved finally in a similar proportion of previously transplanted and other patients (70% vs. 82.6%). Our data suggest that stem cell mobilization with plerixafor and G-CSF might overcome the negative effect of prognostic factors for poor stem cell mobilization in patients with MM who have undergone autoSCT previously.

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