Targeting lysine demethylase 6B ameliorates ASXL1 truncation-mediated myeloid malignancies in preclinical models.

ASXL1 mutation frequently occurs in all forms of myeloid malignancies and is associated with aggressive disease and poor prognosis. ASXL1 recruits Polycomb repressive complex 2 (PRC2) to specific gene loci to repress transcription through trimethylation of histone H3 on lysine 27 (H3K27me3). ASXL1 alterations reduce H3K27me3 levels, which results in leukemogenic gene expression and the development of myeloid malignancies. Standard therapies for myeloid malignancies have limited efficacy when mutated ASXL1 is present. We discovered upregulation of lysine demethylase 6B (KDM6B), a demethylase for H3K27me3, in ASXL1-mutant leukemic cells, which further reduces H3K27me3 levels and facilitates myeloid transformation. Here, we demonstrated that heterozygous deletion of Kdm6b restored H3K27me3 levels and normalized dysregulated gene expression in Asxl1Y588XTg hematopoietic stem/progenitor cells (HSPCs). Furthermore, heterozygous deletion of Kdm6b decreased the HSPC pool, restored their self-renewal capacity, prevented biased myeloid differentiation, and abrogated progression to myeloid malignancies in Asxl1Y588XTg mice. Importantly, administration of GSK-J4, a KDM6B inhibitor, not only restored H3K27me3 levels but also reduced the disease burden in NSG mice xenografted with human ASXL1-mutant leukemic cells in vivo. This preclinical finding provides compelling evidence that targeting KDM6B may be a therapeutic strategy for myeloid malignancies with ASXL1 mutations.

Epigenetic regulation by ASXL1 in myeloid malignancies.

Myeloid malignancies are clonal hematopoietic disorders that are comprised of a spectrum of genetically heterogeneous disorders, including myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML). Myeloid malignancies are characterized by excessive proliferation, abnormal self-renewal, and/or differentiation defects of hematopoietic stem cells (HSCs) and myeloid progenitor cells hematopoietic stem/progenitor cells (HSPCs). Myeloid malignancies can be caused by genetic and epigenetic alterations that provoke key cellular functions, such as self-renewal, proliferation, biased lineage commitment, and differentiation. Advances in next-generation sequencing led to the identification of multiple mutations in myeloid neoplasms, and many new gene mutations were identified as key factors in driving the pathogenesis of myeloid malignancies. The polycomb protein ASXL1 was identified to be frequently mutated in all forms of myeloid malignancies, with mutational frequencies of 20%, 43%, 10%, and 20% in MDS, CMML, MPN, and AML, respectively. Significantly, ASXL1 mutations are associated with a poor prognosis in all forms of myeloid malignancies. The fact that ASXL1 mutations are associated with poor prognosis in patients with CMML, MDS, and AML, points to the possibility that ASXL1 mutation is a key factor in the development of myeloid malignancies. This review summarizes the recent advances in understanding myeloid malignancies with a specific focus on ASXL1 mutations.

Treatment failure and costs in patients with methicillin-resistant Staphylococcus aureus (MRSA) skin and soft tissue infections: a South Texas Ambulatory Research Network (STARNet) study.

OBJECTIVE: To measure the incidence of treatment failure and associated costs in patients with methicillin-resistant Staphylococcus aureus skin and soft tissue infections (SSTIs). METHODS: This was a prospective, observational study in 13 primary care clinics. Primary care providers collected clinical data, wound swabs, and 90-day follow-up information. Patients were considered to have "moderate or complicated" SSTIs if they had a lesion ≥5 cm in diameter or diabetes mellitus. Treatment failure was evaluated within 90 days of the initial visit. Cost estimates were obtained from federal sources. RESULTS: Overall, treatment failure occurred in 21% of patients (21 of 98) at a mean additional cost of $1,933.71 per patient. In a subgroup analysis of patients who received incision and drainage, those with moderate or complicated SSTIs had higher rates of treatment failure than those with mild or uncomplicated SSTIs (36% vs. 10%; P=.04). CONCLUSIONS: One in 5 patients presenting to a primary care clinic for a methicillin-resistant S. aureus SSTI will likely require additional interventions at an associated cost of almost $2,000 per patient. Baseline risk stratification and new treatment approaches are needed to reduce treatment failures and costs in the primary care setting.

Prevalence, severity, and treatment of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) skin and soft tissue infections in 10 medical clinics in Texas: a South Texas Ambulatory Research Network (STARNet) study.

OBJECTIVES: Quantify the prevalence, measure the severity, and describe treatment patterns in patients who present to medical clinics in Texas with community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) skin and soft-tissue infections (SSTI). METHODS: Ten primary care clinics participated in this prospective, community-based study. Clinicians consented patients and collected clinical information, pictures, and wound swabs; data were processed centrally. MRSASelect™ was used for identification. Susceptibilities were determined via Etest®. RESULTS: Overall, 73 of 119 (61%) patients presenting with SSTIs meeting eligibility requirements had CA-MRSA. Among these, 49% were male, 79% were Hispanic, and 30% had diabetes. Half (56%) of the lesions were ≥ 5 cm in diameter. Most patients had abscesses (82%) and many reported pain scores of ≥ 7 of 10 (67%). Many presented with erythema (85%) or drainage (56%). Most received incision and drainage plus an antibiotic (64%). Antibiotic monotherapy was frequently prescribed: trimethoprim-sulfamethoxazole (TMP-SMX) (78%), clindamycin (4%), doxycycline (2%), and mupirocin (2%). The rest received TMP-SMX in combination with other antibiotics. TMP-SMX was frequently administered as one double-strength tablet twice daily. Isolates were 93% susceptible to clindamycin and 100% susceptible to TMP-SMX, doxycycline, vancomycin, and linezolid. CONCLUSIONS: We report a predominance of CA-MRSA SSTIs, favorable antibiotic susceptibilities, and frequent use of TMP-SMX in primary care clinics.