Epigenetic regulator genes direct lineage switching in MLL/AF4 leukemia.

The fusion gene MLL/AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukemia. Relapse can be associated with a lineage switch from acute lymphoblastic to acute myeloid leukemia, resulting in poor clinical outcomes caused by resistance to chemotherapies and immunotherapies. In this study, the myeloid relapses shared oncogene fusion breakpoints with their matched lymphoid presentations and originated from various differentiation stages from immature progenitors through to committed B-cell precursors. Lineage switching is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programs, including alternative splicing. These findings indicate that the execution and maintenance of lymphoid lineage differentiation is impaired. The relapsed myeloid phenotype is recurrently associated with the altered expression, splicing, or mutation of chromatin modifiers, including CHD4 coding for the ATPase/helicase of the nucleosome remodelling and deacetylation complex. Perturbation of CHD4 alone or in combination with other mutated epigenetic modifiers induces myeloid gene expression in MLL/AF4+ cell models, indicating that lineage switching in MLL/AF4 leukemia is driven and maintained by disrupted epigenetic regulation.

In Hospital Outcomes for High-Risk Percutaneous Coronary Intervention (PCI) in Patients Referred From a Rural Centre to Metropolitan Sites.

BACKGROUND: Cardiac Society of Australia and New Zealand (CSANZ) guidelines recommend elective high-risk percutaneous coronary intervention (PCI) is not performed in sites greater than 1 hour from cardiac surgery. METHODS: In hospital outcomes for all patients from Orange Health Service (OHS) from January 2017 to January 2020 who were transferred electively to tertiary centres in Sydney for high risk PCI were examined. RESULTS: One hundred and fourteen (114) patients were identified, with 1,259 PCIs performed at OHS over the same period without transfer. The mean age of these 114 patients was 71 years, with 74.6% male. Receiving hospitals were Royal Prince Alfred Hospital, Sydney, NSW (66.7%), Concord Repatriation General Hospital, Concord, NSW (19.3%) and Strathfield Private Hospital, Strathfield, NSW (14%). The definition of high risk and indication for transfer included at least one of: moderate or greater calcification of the target lesion or proximal segment (34%), single or multiple target lesions that in aggregate jeopardised over 50% of remaining viable myocardium (27%), degenerated saphenous vein grafts (14.8%), chronic total occlusions (7.0%) and severe left ventricular (LV) impairment (3.9%). American Heart Society/American College of Cardiology (AHA/ACC) lesion types were A (1%), B1 (4.2%), B2 (40.2%), and C (54.6%). PCI was performed via the femoral route in 96.2%. The mean procedure duration was 72 minutes, mean combined fluoroscopy time was 19 minutes and mean radiation dose as defined by Reference Air Kerma was 1,630 mGy. Complications occurred in 13 patients and were: acute vessel dissection requiring stenting (4), perforation (2), acute vessel closure (4), puncture site related (1), and life-threatening arrhythmia (2). There were no cases of emergent coronary artery bypass graft (CABG) or death. CONCLUSION: This contemporary cohort of high-risk patients transferred electively from a regional PCI centre to a tertiary cardiac unit underwent lengthy PCI procedures, with high radiation doses, and a modest rate of peri-procedural complications, but had otherwise excellent procedural and clinical outcomes.

Rural and Remote Cardiology During the COVID-19 Pandemic: Cardiac Society of Australia and New Zealand (CSANZ) Consensus Statement.

THE CHALLENGES: Rural and remote Australians and New Zealanders have a higher rate of adverse outcomes due to acute myocardial infarction, driven by many factors. The prevalence of cardiovascular disease (CVD) is also higher in regional and remote populations, and people with known CVD have increased morbidity and mortality from coronavirus disease 2019 (COVID-19). In addition, COVID-19 is associated with serious cardiac manifestations, potentially placing additional demand on limited regional services at a time of diminished visiting metropolitan support with restricted travel. Inter-hospital transfer is currently challenging as receiving centres enact pandemic protocols, creating potential delays, and cardiovascular resources are diverted to increasing intensive care unit (ICU) and emergency department (ED) capacity. Regional and rural centres have limited staff resources, placing cardiac services at risk in the event of staff infection or quarantine during the pandemic. MAIN RECOMMENDATIONS: Health districts, cardiologists and government agencies need to minimise impacts on the already vulnerable cardiovascular health of regional and remote Australians and New Zealanders throughout the COVID-19 pandemic. Changes in management should include.

The ability to cross the blood-cerebrospinal fluid barrier is a generic property of acute lymphoblastic leukemia blasts.

Prevention of central nervous system (CNS) relapse is critical for cure of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Despite this, mechanisms of CNS infiltration are poorly understood, and the timing, frequency, and properties of BCP-ALL blasts entering the CNS compartment are unknown. We investigated the CNS-engrafting potential of BCP-ALL cells xenotransplanted into immunodeficient NOD.Cg- ITALIC! Prkdc (ITALIC! scid) ITALIC! Il2rg (ITALIC! tm1Wjl)/SzJ mice. CNS engraftment was seen in 23 of 29 diagnostic samples (79%): 2 of 2 from patients with overt CNS disease and 21 of 27 from patients thought to be CNS negative by diagnostic lumbar puncture. Histologic findings mimic human pathology and demonstrate that leukemic cells transit the blood-cerebrospinal fluid barrier situated close to the dural sinuses, the site of recently discovered CNS lymphatics. Retrieval of blasts from the CNS showed no evidence for chemokine receptor-mediated selective trafficking. The high frequency of infiltration and lack of selective trafficking led us to postulate that CNS tropism is a generic property of leukemic cells. To test this, we performed serial dilution experiments which showed CNS engraftment in 5 of 6 mice after transplant of as few as 10 leukemic cells. Clonal tracking techniques confirmed the polyclonal nature of CNS-infiltrating cells, with multiple clones engrafting in both the CNS and periphery. Overall, these findings suggest that subclinical seeding of the CNS is likely to be present in most BCP-ALL patients at original diagnosis, and efforts to prevent CNS relapse should concentrate on effective eradication of disease from this site rather than targeting entry mechanisms.

CD19: A multifunctional immunological target molecule and its implications for Blineage acute lymphoblastic leukemia.

Over the last 20-30 years CD19 has gained attention as a potential target in the therapy of B-cell malignancies. In particular, targeting CD19 with the bispecific T-cell engager (BiTE) antibody Blinatumomab and T-cells modified by chimeric antigen receptors (CAR) has shown promising efficacy in early phase clinical trials for adults and children with precursor B-cell ALL (BCP-ALL). This review will discuss the rationale behind targeting CD19 in BCP-ALL and its potential importance in BCP-ALL signaling pathways.

The Oncogenic Transcription Factor RUNX1/ETO Corrupts Cell Cycle Regulation to Drive Leukemic Transformation.

Oncogenic transcription factors such as the leukemic fusion protein RUNX1/ETO, which drives t(8;21) acute myeloid leukemia (AML), constitute cancer-specific but highly challenging therapeutic targets. We used epigenomic profiling data for an RNAi screen to interrogate the transcriptional network maintaining t(8;21) AML. This strategy identified Cyclin D2 (CCND2) as a crucial transmitter of RUNX1/ETO-driven leukemic propagation. RUNX1/ETO cooperates with AP-1 to drive CCND2 expression. Knockdown or pharmacological inhibition of CCND2 by an approved drug significantly impairs leukemic expansion of patient-derived AML cells and engraftment in immunodeficient murine hosts. Our data demonstrate that RUNX1/ETO maintains leukemia by promoting cell cycle progression and identifies G1 CCND-CDK complexes as promising therapeutic targets for treatment of RUNX1/ETO-driven AML.