Convergent organization of aberrant MYB complex controls oncogenic gene expression in acute myeloid leukemia.

Dysregulated gene expression contributes to most prevalent features in human cancers. Here, we show that most subtypes of acute myeloid leukemia (AML) depend on the aberrant assembly of MYB transcriptional co-activator complex. By rapid and selective peptidomimetic interference with the binding of CBP/P300 to MYB, but not CREB or MLL1, we find that the leukemic functions of MYB are mediated by CBP/P300 co-activation of a distinct set of transcription factor complexes. These MYB complexes assemble aberrantly with LYL1, E2A, C/EBP family members, LMO2, and SATB1. They are organized convergently in genetically diverse subtypes of AML and are at least in part associated with inappropriate transcription factor co-expression. Peptidomimetic remodeling of oncogenic MYB complexes is accompanied by specific proteolysis and dynamic redistribution of CBP/P300 with alternative transcription factors such as RUNX1 to induce myeloid differentiation and apoptosis. Thus, aberrant assembly and sequestration of MYB:CBP/P300 complexes provide a unifying mechanism of oncogenic gene expression in AML. This work establishes a compelling strategy for their pharmacologic reprogramming and therapeutic targeting for diverse leukemias and possibly other human cancers caused by dysregulated gene control.

[Role of ASXL1 mutations in hematological disorders].

Recent progress in whole genome sequencing has identified recurrent somatic mutations in the additional sex combs like 1 (ASXL1) gene in a variety of hematological disorders and even in premalignant conditions. However, the molecular mechanisms regarding the contribution of ASXL1 mutation to the pathogenesis of premalignant conditions remain largely unelucidated. Thus, we investigated the biological effects of mutant Asxl1 using newly-generated knock-in (KI) mice. Heterozygous mutant KI mice developed phenotypes resembling human low-risk myelodysplastic syndromes (MDS), and some of them developed an MDS/myeloproliferative neoplasm-like disease after a long latency. The H2AK119ub1 level around the promoter region of p16Ink4a was significantly decreased in KI hematopoietic stem cells (HSCs), suggesting perturbation of Bmi1-driven H2AK119ub1 histone modification by mutant Asxl1. The mutant Asxl1 failed to interact with Bmi1, although wild type ASXL1 protein did not. When p16Ink4a expression was depleted in Asxl1 KI mice, the HSC pool was restored, and apoptosis was ameliorated in HSCs. These findings demonstrate that the loss of protein interaction between mutant Asxl1 and Bmi1 affected the activity of Prc1. The subsequent derepression of p16Ink4a by aberrant histone ubiquitination could induce cellular senescence, resulting in low-risk MDS-like phenotypes in heterozygous Asxl1 KI mice.

Modeling ASXL1 mutation revealed impaired hematopoiesis caused by derepression of p16Ink4a through aberrant PRC1-mediated histone modification.

In spite of distinct clinical importance, the molecular mechanisms how Additional sex combs-like 1 (ASXL1) mutation contributes to the pathogenesis of premalignant conditions are largely unknown. Here, with newly generated knock-in mice, we investigated the biological effects of the mutant. Asxl1G643fs heterozygous (Asxl1G643fs/+) mice developed phenotypes recapitulating human low-risk myelodysplastic syndromes (MDS), and some of them developed MDS/myeloproliferative neoplasm-like disease after long latency. H2AK119ub1 level around the promoter region of p16Ink4a was significantly decreased in Asxl1G643fs/+ hematopoietic stem cells (HSC), suggesting perturbation of Bmi1-driven H2AK119ub1 histone modification by mutated Asxl1. The mutant form of ASXL1 had no ability to interact with BMI1 as opposed to wild-type ASXL1 protein. Restoration of HSC pool and amelioration of increased apoptosis in hematopoietic stem and progenitor cells were obtained from Asxl1G643fs/+ mice heterozygous for p16Ink4a. These results indicated that loss of protein interaction between Asxl1 mutant and Bmi1 affected the activity of PRC1, and subsequent derepression of p16Ink4a by aberrant histone ubiquitination could induce cellular senescence, resulting in low-risk MDS-like phenotypes in Asxl1G643fs/+ mice. This model provides a useful platform to unveil the molecular basis for hematological disorders induced by ASXL1 mutation and to develop therapeutic strategies for these patients.

Efficacy of early switch from intravenous to oral antimicrobials in patients with aspiration pneumonia: A prospective observational study.

BACKGROUND: Previous reports have documented the efficacy of an early switch from intravenous to oral antimicrobials in community-acquired pneumonia, but not aspiration pneumonia. Therefore, we assessed the feasibility and efficacy of these newly developed criteria for community-acquired pneumonia in patients with aspiration pneumonia. METHODS: This prospective observational study included consecutive patients admitted with aspiration pneumonia over a 10-month period at St. Luke's International Hospital; we excluded patients that required intensive care. The criteria for an early switch were stability of vital signs (temperature ≤ 38 °C; respiratory rate ≤ 24 breaths/min; pulse rate ≤ 100 beats/min for >24 h) and a successful swallow evaluation (repetitive saliva swallowing test score ≥ 2; modified water swallowing test score ≥ 4). Our primary endpoint was successful completion of antimicrobial treatment 30 days after the switch, without reversion to intravenous antimicrobials. Our anticipated success rate was set as 60-75%, based on a previous study. RESULTS: Of the 70 patients admitted with aspiration pneumonia, 32 (45.7%) were excluded, and 38 (54.3%) met the inclusion criteria. Of these 38 patients, 29 (76.3%) met the switch criteria. The median duration of hospital stay for the included patients was 16 (5-30) days and 30 (12-68) days, respectively (P=0.03). Among patients who met the switch criteria, 26 (89.7%) completed oral treatment successfully while 3 (10.3%) reverted to intravenous antimicrobials. CONCLUSIONS: Approximately 75% of patients met the switch criteria; of these, nearly 90% underwent safe conversion to oral therapy. These results demonstrate the efficacy and feasibility of our switch criteria.

Comparison of garenoxacin with levofloxacin as antimicrobial prophylaxis in acute myeloid leukemia.

OBJECTIVE: Levofloxacin is widely used as antimicrobial prophylaxis against high-risk chemotherapy-induced neutropenia. Garenoxacin, a fluoroquinolone developed in Japan, shows a stronger in vitro antimicrobial activity against Gram-positive bacteria than levofloxacin. METHODS: We retrospectively analyzed high-risk patients with acute myeloid leukemia who were administered garenoxacin (n = 36) or levofloxacin (n = 120) during chemotherapy. We compared the profiles of infections between these fluoroquinolones. RESULTS: Febrile events occurred in 31 (86%) and 93 (78%) cases in the garenoxacin and levofloxacin group, respectively (P = 0.35). Bloodstream infections by Gram-positive bacteria were recorded in one (3%) case in the garenoxacin group and 25 (21%) cases in the levofloxacin group (P < 0.01). In contrast, bloodstream infections by Gram-negative microorganisms were identified in five (4%) cases in the levofloxacin group and eight (22%) cases in the garenoxacin group (P < 0.01). CONCLUSIONS: These results indicate that there may be substantial differences in the antimicrobial spectrum between different fluoroquinolones. Although there are several biases due to rather small sample size and the retrospective nature, we should take the differences into consideration when we administer a prophylactic fluoroquinolone to a patient with hematological disease.

Transformation of follicular lymphoma in the retroperitoneal muscles demonstrated by CT-guided needle biopsy of FDG-avid lesions; case series.

We herein report two cases of relapsed follicular lymphoma (FL) with transformation in the retroperitoneal muscles. Fluorodeoxyglucose (FDG)-positron emission tomography (PET) combined with computed tomography (CT) showed high uptakes in the retroperitoneal muscles. We considered excisional biopsy at first, since it is definitely the most reliable means to obtain histological diagnosis. However, excisional biopsy of the retroperitoneal muscles is challenging for anatomical reasons. Moreover, our patients were kept under poor performance status. Thus, CT-guided percutaneous needle biopsy of FDG-avid retroperitoneal muscles was performed. Histopathological examination of the biopsied specimens demonstrated proliferation of transformed large B cells in both cases. Sheets of large B cells were also recorded in one case. CT-guided needle biopsy is less prioritized than excisional biopsy because of limited information on tissue architecture and increasingly complicated WHO classification. Our series indicate that image-guided needle biopsy of FDG-avid lesions is sufficient for the diagnosis of transformation. Higher priority should be given to this method in the setting of transformed aggressive lymphoma.

Successful treatment with recombinant thrombomodulin for B-cell lymphoma-associated hemophagocytic syndrome complicated by disseminated intravascular coagulation.

We report here a 47-year-old male with the diagnosis of high-grade B-cell lymphoma and hemophagocytosis accompanying disseminated intravascular coagulation (DIC). Lymphoma-associated hemophagocytic syndrome (LAHS) is a life-threatening disorder, and LAHS secondary to B-cell lymphoma is relatively rare compared to that secondary to T- or NK/T-cell lymphoma in Western countries. T- or NK/T-cell LAHS is sometimes combined with DIC, which makes patients' outcomes even worse, but few reports of B-cell LAHS accompanying DIC has been published so far. We successfully treated a patient with this condition with recombinant thrombomodulin (rTM), a novel agent for DIC. We believe that rTM is a therapeutic option in cases with B-cell LAHS accompanying DIC.