5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) play a critical role in development and normal physiology. Alterations in 5-mC and 5-hmC patterns are common events in hematopoietic neoplasms. In this review, we begin by emphasizing the importance of 5-mC, 5-hmC, and their enzymatic modifiers in hematological malignancies. Then, we discuss the functions of 5-mC and 5-hmC at distinct genic contexts, including promoter regions, gene bodies, intron-exon boundaries, alternative promoters, and intragenic microRNAs. Recent advances in technology have allowed for the study of 5-mC and 5-hmC independently and specifically permitting distinction between the bases that show them to have transcriptional effects that vary by their location relative to gene structure. We extend these observations to their functions at enhancers and transcription factor binding sites. We discuss dietary influences on 5-mC and 5-hmC levels and summarize the literature on the effects of folate and vitamin C on 5-mC and 5-hmC, respectively. Finally, we discuss how these new themes in the functions of 5-mC and 5-hmC will likely influence the broader research field of epigenetics.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic neoplasm resulting from the malignant transformation of T-cell progenitors, and comprises approximately 15% and 25% of pediatric and adult ALL cases respectively. It is well-established that activating NOTCH1 mutations are the major genetic lesions driving T-ALL in most patients, but efforts to develop targeted therapies against this pathway have produced limited success in decreasing leukemic burden and come with significant clinical side effects. A finer detailed understanding of the genetic and molecular mechanisms underlying T-ALL is required identify patients at increased risk for treatment failure and the development of precision medicine strategies. Generation of genetic models that more accurately reflect the normal developmental history of T-ALL are necessary to identify new avenues for treatment. The DNA methyltransferase enzyme DNMT3A is also recurrently mutated in T-ALL patients, and we show here that inactivation of Dnmt3a combined with Notch1 gain-of-function leads to an aggressive T-ALL in mouse models. Moreover, conditional inactivation of Dnmt3a in mouse hematopoietic cells leads to an accumulation of immature progenitors in the thymus which are less apoptotic. These data demonstrate that Dnmt3a is required for normal T-cell development, and acts as a T-ALL tumor suppressor.
Purpose: Optimal management of isolated local recurrences after stereotactic body radiation therapy (SBRT) for early non-small cell lung cancer (NSCLC) is unknown and literature describing repeat SBRT for in-field recurrences after initial SBRT are sparse. We investigate the safety and efficacy of salvage SBRT for isolated local failures after initial SBRT for NSCLC.Methods/Materials: Patients receiving SBRT for isolated local recurrence after initial SBRT for early NSCLC were identified using a prospective registry. Both courses were 3-5 fractions with a biologically effective dose (BED10) of ≥100Gy. Local failure was defined as within 1 cm of the initial planning target volume (PTV) or an overlap of the ≥25% isodose lines of the first and second treatments. Failures >1 cm beyond the PTV and without ≥25% overlap, or with additional recurrence sites were excluded. Kaplan-Meier analysis was used to estimate survival. Results:A total 21 patients receiving salvage SBRT from 2008 to 2017 were identified. Median interval from initial SBRT to salvage SBRT was 23 months (7-52). Six patients (29%) had central tumors. Median follow-up time from salvage SBRT was 24 months (3-60). Median overall survival after salvage was 39 months. After reirradiation, two-year primary tumor control was 81%, regional nodal control was 89%, distant control was 75% and overall survival was 68%. Grade 2 pneumonitis occurred in 2 patients (10%) and grade 2 chest wall toxicity in 4 patients (19%). No grade 3+ toxicity was observed.Conclusions: Salvage SBRT for isolated local failures after initial SBRT appears safe, with low treatment-related toxicity and encouraging rates of tumor control.
Background: Patients with multiple primary lung cancers (MPLC) increasingly receive multiple courses of stereotactic body radiation therapy (SBRT). We aimed to clarify the efficacy and safety of such treatments. Patients and Methods: We reviewed a prospective lung SBRT database for patients treated for stage I non-small cell lung cancer between June 2004 and December 2015. Results: 374 patients received a single course of SBRT, 14 received synchronous SBRT, 48 received metachronous SBRT alone, and 108 received surgery and metachronous SBRT. Median follow-up was 37.0 months for survivors. Patients that received a single course had a three-year overall survival (OS) of 54.2% (95% confidence interval [CI], 48.8-59.3%), three-year freedom from progression (FFP) of 67.3% (95% CI, 60.9-72.9), and grade ≥3 toxicity of 3.5%. Compared to single-course patients, patients receiving metachronous SBRT alone and patients receiving surgery and metachronous SBRT had improved OS (79.
Background: There is increasing interest in treating oligometastatic non-small cell lung cancer (NSCLC) patients with stereotactic radiation. We aimed to address whether patients definitively treated with synchronous thoracic stereotactic body radiation therapy (SBRT) and brain stereotactic radiosurgery (SRS) had favorable outcomes with local therapy. Materials and methods: We reviewed a database of patients receiving lung SBRT as well as a database for brain metastasis patients treated with SRS between June 2004 and January 2016. We selected for cT1-2aN0M1 NSCLC patients with brain metastases and calculated their overall survival (OS), freedom from progression (FFP), and local control (LC) rates. Results: Six patients had oligometastatic NSCLC with 1-3 synchronous brain metastases treated with lung SBRT and brain SRS. No patients received immunotherapy and two-thirds did not receive systemic therapy. Median follow-up was 9 months for the entire cohort (range, 2-95 months) and 95 months for the surviving patient. Median OS was 12.4 months (95% confidence interval [CI], 7-18 months). At 1 year, patients had 67% OS (95% CI, 29-100%), 17% FFP (95% CI, 0-46%), and 100% LC. Their brain disease had 80% 1-year LC (95% CI, 45-100%) and 53% 1-year FFP (95% CI, 5-100%). Two patients had no distant progression, two had brain progression, one had adrenal gland progression, and one had bone and liver progression. Conclusion: In patients presenting with oligometastatic lung cancer limited to the brain, treatment with both lung SBRT and brain SRS achieves good LC of all sites with encouraging OS.
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