Outcomes of children and young adults with T-cell acute lymphoblastic leukemia/lymphoma who present in critical status.

BACKGROUND: Patients with T-cell acute lymphoblastic leukemia and lymphoma (T-ALL/LLy) commonly present with critical features such as hyperleukocytosis and mediastinal mass, which complicates completing a diagnostic and staging workup and prevents clinical trial enrollment. PROCEDURE: Consecutive patients with T-ALL/LLy from 1999 to 2019 at the Children's Hospital of Philadelphia were analyzed for pediatric intensive care unit (PICU) admission and various high-risk features as well as clinical trial enrollment and outcome. RESULTS: We identified 153 patients newly diagnosed with T-ALL/LLy, 53 (35%) required PICU-level care within 24 hours and 73 (48%) within 7 days. Non-PICU patients had a significantly higher clinical trial enrollment rate (79.4%) versus PICU patients (56.1%, P = 0.016). Patients who enrolled on a clinical trial had similar relapse risk to those who did not enroll (relapse rate 20% vs 29%, P = 0.523). Nineteen patients were precluded from trial participation. Risk of relapse was increased for patients admitted to the PICU within 24 hours (26% vs 13%, P = 0.048). Forty-four patients with T-ALL presented with hyperleukocytosis, of which 30% relapsed versus 14% without (P = 0.082). Patients who underwent apheresis for hyperleukocytosis were statistically more likely to relapse (47% vs 15%, P = 0.007). Patients with elevated uric acid (20% vs 16%, P = 0.278), mediastinal mass (20% vs 14%, P = 0.501), or required emergent steroids (20% vs 16%, P = 0.626) had a similar relapse risk. A single second relapse patient survived. CONCLUSIONS: Almost half of T-ALL/LLy patients required PICU-level care at diagnosis, making enrollment on clinical trials challenging, but trial enrollment predicted better outcome. Physicians should balance maintaining eligibility with safety to offer patients all options.

Huntingtin Polyglutamine Fragments Are a Substrate for Hsp104 in Saccharomyces cerevisiae.

The aggregation of huntingtin fragments with expanded polyglutamine repeat regions (HttpolyQ) that cause Huntington's disease depends on the presence of a prion with an amyloid conformation in yeast. As a result of this relationship, HttpolyQ aggregation indirectly depends on Hsp104 due to its essential role in prion propagation. We find that HttQ103 aggregation is directly affected by Hsp104 with and without the presence of [RNQ+] and [PSI+] prions. When we inactivate Hsp104 in the presence of prion, yeast cells have only one or a few large HttQ103 aggregates rather than numerous smaller aggregates. When we inactivate Hsp104 in the absence of prion, there is no significant aggregation of HttQ103, whereas with active Hsp104, HttQ103 aggregates accumulate slowly due to the severing of spontaneously nucleated aggregates by Hsp104. We do not observe either effect with HttQ103P, which has a polyproline-rich region downstream of the polyglutamine region, because HttQ103P does not spontaneously nucleate and Hsp104 does not efficiently sever the prion-nucleated HttQ103P aggregates. Therefore, the only role of Hsp104 in HttQ103P aggregation is to propagate yeast prion. In conclusion, because Hsp104 efficiently severs the HttQ103 aggregates but not HttQ103P aggregates, it has a marked effect on the aggregation of HttQ103 but not HttQ103P.

The histone demethylase Kdm6b regulates a mature gene expression program in differentiating cerebellar granule neurons.

The histone H3 lysine 27 (H3K27) demethylase Kdm6b (Jmjd3) can promote cellular differentiation, however its physiological functions in neurons remain to be fully determined. We studied the expression and function of Kdm6b in differentiating granule neurons of the developing postnatal mouse cerebellum. At postnatal day 7, Kdm6b is expressed throughout the layers of the developing cerebellar cortex, but its expression is upregulated in newborn cerebellar granule neurons (CGNs). Atoh1-Cre mediated conditional knockout of Kdm6b in CGN precursors either alone or in combination with Kdm6a did not disturb the gross morphological development of the cerebellum. Furthermore, RNAi-mediated knockdown of Kdm6b in cultured CGN precursors did not alter the induced expression of early neuronal marker genes upon cell cycle exit. By contrast, knockdown of Kdm6b significantly impaired the induction of a mature neuronal gene expression program, which includes gene products required for functional synapse maturation. Loss of Kdm6b also impaired the ability of Brain-Derived Neurotrophic Factor (BDNF) to induce expression of Grin2c and Tiam1 in maturing CGNs. Taken together, these data reveal a previously unknown role for Kdm6b in the postmitotic stages of CGN maturation and suggest that Kdm6b may work, at least in part, by a transcriptional mechanism that promotes gene sensitivity to regulation by BDNF.