Frontline Ph-negative B-cell precursor acute lymphoblastic leukemia treatment and the emerging role of blinatumomab.

This narrative review seeks to summarize chemotherapeutic regimens commonly used for patients with newly diagnosed Philadelphia (Ph) chromosome-negative B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in the frontline setting and to describe the latest clinical research using the bispecific T-cell-engaging immunotherapy blinatumomab in the first-line treatment setting. Current standard-of-care chemotherapeutic backbones for newly diagnosed Ph-negative BCP-ALL are based on the same overarching treatment principle: to reduce disease burden to undetectable levels and maintain lasting remission. The adult treatment landscape has progressively evolved following the adoption of pediatric-inspired regimens.

Incidence of CD19-negative relapse after CD19-targeted immunotherapy in R/R BCP acute lymphoblastic leukemia: a review.

There are inconsistencies in the reporting of CD19 antigen status following treatment with CD19-targeted therapies. A majority of evidence comes from studies reporting small sample sizes. In this review, we systematically summarize published studies that have reported rates of CD19-negative relapse after treatment with either blinatumomab or CD19-directed CAR T-cell therapy and report the rates of CD19-negative relapse when evaluated in a standardized way across trials.

Deficiency of the metabolic enzyme SCHAD in pancreatic β-cells promotes amino acid-sensitive hypoglycemia.

Congenital hyperinsulinism of infancy (CHI) can be caused by a deficiency of the ubiquitously expressed enzyme short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD). To test the hypothesis that SCHAD-CHI arises from a specific defect in pancreatic β-cells, we created genetically engineered β-cell-specific (β-SKO) or hepatocyte-specific (L-SKO) SCHAD knockout mice. While L-SKO mice were normoglycemic, plasma glucose in β-SKO animals was significantly reduced in the random-fed state, after overnight fasting, and following refeeding.

An N-terminal SIAH-interacting motif regulates the stability of the ubiquitin specific protease (USP)-19.

The Ubiquitin Specific Protease-19 (USP19) regulates cell cycle progression and is involved in the cellular response to different types of stress, including the unfolded protein response (UPR), hypoxia and muscle atrophy. Using the unique N-terminal domain as bait in a yeast-two hybrid screen we have identified the ubiquitin ligases Seven In Absentia Homolog (SIAH)-1 and SIAH2 as binding partners of USP19. The interaction is mediated by a SIAH-consensus binding motif and promotes USP19 ubiquitylation and proteasome-dependent degradation.

The ubiquitin specific protease-4 (USP4) interacts with the S9/Rpn6 subunit of the proteasome.

The proteasome is the major non-lysosomal proteolytic machine in cells that, through degradation of ubiquitylated substrates, regulates virtually all cellular functions. Numerous accessory proteins influence the activity of the proteasome by recruiting or deubiquitylating proteasomal substrates, or by maintaining the integrity of the complex. Here we show that the ubiquitin specific protease (USP)-4, a deubiquitylating enzyme with specificity for both Lys48 and Lys63 ubiquitin chains, interacts with the S9/Rpn6 subunit of the proteasome via an internal ubiquitin-like (UBL) domain.

Ubiquitin-specific protease 19 (USP19) regulates hypoxia-inducible factor 1α (HIF-1α) during hypoxia.

A proper cellular adaptation to low oxygen levels is essential for processes such as development, growth, metabolism, and angiogenesis. The response to decrease in oxygen supply, referred to as hypoxia, is also involved in numerous human diseases including cancer, inflammatory conditions, and vascular disease. The hypoxia-inducible factor 1-α (HIF-1α), a key player in the hypoxic response, is kept under stringent regulation.