Updates in KMT2A Gene Rearrangement in Pediatric Acute Lymphoblastic Leukemia.

The KMT2A (formerly MLL) encodes the histone lysine-specific N-methyltransferase 2A and is mapped on chromosome 11q23. KMT2A is a frequent target for recurrent translocations in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or mixed lineage (biphenotypic) leukemia (MLL). Over 90 KMT2A fusion partners have been identified until now, including the most recurring ones-AFF1, MLLT1, and MLLT3-which encode proteins regulating epigenetic mechanisms. The presence of distinct KMT2A rearrangements is an independent dismal prognostic factor, while very few KMT2A rearrangements display either a good or intermediate outcome. KMT2A-rearranged (KMT2A-r) ALL affects more than 70% of new ALL diagnoses in infants (<1 year of age), 5-6% of pediatric cases, and 15% of adult cases. KMT2A-rearranged (KMT2A-r) ALL is characterized by hyperleukocytosis, a relatively high incidence of central nervous system (CNS) involvement, an aggressive course with early relapse, and early relapses resulting in poor prognosis. The exact pathways of fusions and the effects on the final phenotypic activity of the disease are still subjects of much research. Future trials could consider the inclusion of targeted immunotherapeutic agents and prioritize the identification of prognostic factors, allowing for the less intensive treatment of some infants with KMT2A ALL. The aim of this review is to summarize our knowledge and present current insight into the mechanisms of KMT2A-r ALL, portray their characteristics, discuss the clinical outcome along with risk stratification, and present novel therapeutic strategies.

Piperacillin-Tazobactam Induced Rapid Severe Thrombocytopenia Without Known Exposure.

Thrombocytopenia is one of the commonly encountered laboratory abnormalities in the inpatient setting. The process of excluding life-threatening causes can be daunting and may result in overlooking iatrogenic sources such as medications. Antibiotics are known culprits; however, there are limited reports of rapid and severe onset thrombocytopenia following piperacillin-tazobactam (TZP) that were frequently observed in critically ill or immunocompromised patients with previous exposure to the antibiotic. This case describes a patient being treated for a soft tissue infection with vancomycin and TZP. Initiation of antimicrobial therapy resulted in severe thrombocytopenia and a platelet nadir of approximately 4,000 within 24 hours of the first doses. Thrombocytopenia resolved within three days of TZP withdrawal. To the best of our knowledge, there have not been any cases described of rapid drug-induced thrombocytopenia without previous exposure to the medication. Medications should always be reviewed when evaluating a patient with rapid and severe thrombocytopenia, which can obviate the need for unnecessary invasive or non-invasive treatments.

Cardioprotection by triiodothyronine following caloric restriction via long noncoding RNAs.

Severe caloric-restriction compromises thyroid hormone (TH) status, apparently to save energy and proteins for enduring stress stimulus. However, a persistent decrease in TH levels may compromise heart function. We hypothesized that supplementation of low dose active TH or targeting hypoxia-inducible factor-1-alpha, HIF-1α (a strong activator of deiodinase enzyme that degrades peripheral active THs) will prevent deterioration of cardiac performance. Adult mice were subjected to acute fasting based on institutional animal protocols with ad libitum access to water. The following groups were studied: Control mice with free access to food; severe caloric restriction fasting only group; Fasting with Triiodo-l-Thyronine (T3); Fasting with HIF-1α inhibitor (BAY). Cardiac hemodynamic and electrophysiological studies were performed and role of long noncoding RNAs were explored. Following severe caloric-restriction, we found that body weights, and heart weights to a partial extent, were decreased. Low-dose T3 treatment attenuated left ventricular hemodynamic impairment in indices of cardiac contractility and relaxation. In electrophysiology studies, fasting mice developed atrial tachyarrhythmias upon induction. This reverted to control levels following T3 treatment. There was a significant increase in atrioventricular conduction time and significant decrease in heart rate following fasting. Both these changes were attenuated following T3 treatment. Furthermore, BAY partially improved hemodynamics. Compared to the severe caloric-restriction group, both T3 and BAY reduced MALAT1 and GAS5 long noncoding RNA expression. These new findings indicate that T3 and BAY protect from cardiac decompensation secondary to acute severe caloric-restriction partly mediated by long noncoding RNAs.