Research Update: NFkB, Autophagy, and Asparaginase-Associated Pancreatitis

Amitava Mukherjee, PhD, is a research instructor in the Division of Pediatric Gastroenterology, Hepatology, and Nutrition. A cell and molecular biologist, Dr. Mukherjee specializes in the study of the molecular drivers of protein turnover, cellular homeostasis, and proteotoxicity. For the past two years he also has been interested in various cellular autophagic processes related to the development of asparaginase-associated pancreatitis (AAP) in the treatment of acute lymphoblastic leukemia (ALL). Dr. Mukherjee, in collaboration with former chair of the Department of Pediatrics, David H. Perlmutter, MD, has spent many years investigating the roles of the protein a1-antitrypsin in proteinopathy that drive fibrosis and cancer in the liver.

Dr. Mukherjee and colleagues recently published findings in the journal Cell Death & Differentiation identifying the role of the NFkB signaling pathway with respect to dysregulation and misfolding of the a1-antitrypsin protein.

“The primary function of a1-antitriyspin is in the lungs where it neutralizes neutrophil hydrolysis. Dysregulation and misfolding of the protein cause it to essentially become stuck in the endoplasmic reticulum (ER) of the liver cell. This leads to a two-fold problem. The lungs need this protein to help protect them against emphysema. In the liver, hepatocytes end up with an overload of misfolded a1-antitrypsin. Accumulation of this misfolded protein leads to fibrosis and liver damage, and ultimately it can be responsible for the development of some liver cancers,” explains Dr. Mukherjee.

The recently published paper showed that the nuclear transcription factor NFkB, which is involved in many cellular processes, has a protective effect in the liver through two mechanisms. It protects the liver hepatocytes from fibrosis, and it also induces an autophagic response to target and clear the misfolded a1-antitrypsin proteins.

“We were able to show that NFkB signaling leads to autophagy, and autophagy leads to fewer accumulated misfolded proteins inside the ER of the liver cells. NFkB also is responsible for activating a process that degrades fibrotic protein collagen accumulation in the extracelluar matrix of the liver. Now we are excited to begin to explore how exactly NFkB induces autophagy. That will be our next target of investigation,” says Dr. Mukherjee.

New Award to Study Asparaginase- Associated Pancreatitis

In June, Dr. Mukherjee was awarded a UPMC Children’s Rangos Advisory Committee (RAC) start-up award to support his research into the pathogenesis of asparaginase-associated pancreatitis. The RAC award is a two-year grant that is designed to support junior faculty in their progress toward becoming independent investigators.

Asparaginase is a first-line, crucial therapeutic agent for the treatment of acute lymphoblastic leukemia (ALL). In some patients, however, treatment with asparaginase can lead to acute pancreatitis with high rates of morbidity and mortality. Dr. Mukherjee’s research, in collaboration with Sohail Husain, MD, seeks to understand why only a small percentage of asparaginase-treated patients develop the condition, and what mechanisms are driving its induction. “We think some patients could be lacking in production of asparagine synthetase in the pancreas, which is a protein that helps counteract the reduction in the amino acid asparagine that is selectively targeted by asparaginase in the treatment of ALL. The other theory is that there is dysregulation of autophagic processes in the pancreas of these patients that leads to amino acid imbalances at the cellular level, eventually leading to injury of the pancreas and pancreatitis,” says Dr. Mukherjee.

Dr. Mukherjee’s investigations will attempt to determine whether asparagine synthetase does in fact play a protective role in pancreas cells, as well as whether dysregulation of the normal autophagy process is a contributing factor. If this is the case, the research could point to potential therapeutic targets and further drug discovery avenues to develop a means to either treat cases of AAP after they arise or even potentially derive a combinative therapy delivered at the time of asparaginase therapy as a matter of prophylaxis.

Further Reading

Mukherjee A, Hidvegi T, Araya P, Ewing M, Stolz DB, Perlmutter DH. NFkB Mitigates the Pathological Effects of Misfolded a1-Antitrypsin by Activating Autophagy and an Integrated Program of Proteostasis Mechanisms. Cell Death Differ. 2018 May 23. Epub ahead of print.