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During the essential and conserved process of zygotic genome activation (ZGA), chromatin accessibility must increase to promote transcription. Drosophila is a well-established model for defining mechanisms that drive ZGA. Zelda (ZLD) is a key pioneer transcription factor (TF) that promotes ZGA in the Drosophila embryo. However, many genomic loci that contain GArich motifs become accessible during ZGA independent of ZLD. Therefore, we hypothesized that other early TFs that function with ZLD have not yet been identified, especially those that are capable of binding to GA-rich motifs such as chromatin-linked adaptor for male-specific lethal (MSL) proteins (CLAMP). Here, we demonstrate that Drosophila embryonic development requires maternal CLAMP to (1) activate zygotic transcription; (2) increase chromatin accessibility at promoters of specific genes that often encode other essential TFs; and (3) enhance chromatin accessibility and facilitate ZLD occupancy at a subset of key embryonic promoters. Thus, CLAMP functions as a pioneer factor that plays a targeted yet essential role in ZGA. [ABSTRACT FROM AUTHOR]

In this prospective, multicenter, phase 2 study, 64 patients with relapsed or relapsed and refractory multiple myeloma (MM) received up to 8 21-day cycles of bortezomib 1.0 mg/m2 (days 1,4,8, and 11), lenalidomide 15 mg/day (days 1 -14), and dexamethasone 40/20 mg/day (cycles 1-4) and 20/10 mg/day (cycles 5-8) (days of/after bortezomib dosing). Responding patients could receive maintenance therapy. Median age was 65 years; 66% were male, 58% had relapsed and 42% had relapsed and refractory MM, and 53%, 75%, and 6% had received prior bortezomib, thalidomide, and lenalidomide, respectively. Forty-eight of 64 patients (75%; 90% confidence interval, 65-84) were alive without progressive disease at 6 months (primary end point). The rate of partial response or better was 64%; median duration of response was 8.7 months. Median progression-free and overall survivals were 9.5 and 30 months, respectively (median follow-up: 44 months). Common treatment-related toxicities included sensory neuropathy (53%), fatigue (50%), and neutropenia (42%); common grade 3/4 treatment-related toxicities included neutropenia (30%), thrombocytopenia (22%), and lymphopenia (11%). Grade 3 motor neuropathy was reported in 2 patients. Lenalidomide-bortezomib-dexamethasone appears effective and tolerable in patients with relapsed or relapsed and refractory MM, demonstrating substantial activity among patients with diverse prior therapies and adverse prognostic characteristics. [ABSTRACT FROM AUTHOR]

We present the case of a woman with relapsed multiple myeloma (MM) who received combination lenalidomide and bortezomib therapy for 90 cycles followed by continuous lenalidomide monotherapy and has completed over 100 cycles of treatment to date. The patient was diagnosed with advanced-stage, symptomatic MM in 2001. Following a partial response (PR) to dexamethasone in combination with pamidronate and thalidomide, the patient underwent protocol-directed non-myeloablative allogeneic bone marrow transplantation from her matched sibling donor the following year. In 2004, the patient relapsed and was enrolled in a phase I, dose-escalation trial of lenalidomide plus bortezomib for relapsed and refractory MM. After eight cycles of study treatment, the patient achieved a minimal response. The patient received a total of 90 cycles of treatment with lenalidomide 5 mg given for 14 d every 21 d, and 1 mg/m2 of bortezomib initially given on days 1, 4, 8, and 11 for the first 20 cycles, and then weekly thereafter on days 1 and 8. Bortezomib was discontinued after 90 cycles, and the patient continued to receive lenalidomide monotherapy. As of cycle 100, the patient achieved a PR. Currently, she is clinically stable with response sustained for over 7 yrs. Therapy has been well tolerated with no significant long-term toxicity; no dose reductions of lenalidomide and bortezomib were required. The excellent tolerability of this steroid-free approach and the durable response seen underscore the potential benefits of participating in early-phase clinical trials evaluating novel therapies and new drug combinations. This case further supports that combination treatment with lenalidomide and bortezomib is an effective therapy in the management of patients with relapsed and refractory MM. [ABSTRACT FROM AUTHOR]