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Spontaneous Combustion: Extinguishing the Myeloid Inflammatory Milieu

December 10, 2022
Idoroenyi Amanam, MD, and Amanda Blackmon, DO

Dr. Amanda Blackmon (@mlblack1_b) returns this year after serving as a Junior Author in 2021. Originally from Gaithersburg, Maryland, she attended the University of Maryland for undergrad, earned her MS at Georgetown University, and attended medical school at the Philadelphia College of Osteopathic Medicine in Philadelphia. After her residency at Pennsylvania Hospital, Dr. Blackmon headed west for fellowships at University of California Irvine, and City of Hope National Medical Center in Duarte. She is currently an assistant professor of leukemia and hematopoietic cell transplantation at City of Hope, where she focuses on leukemia, myelodysplastic syndromes, and transplantation. She lives in Pasadena, where she is “enjoying the craziness of a dual physician family with a toddler.” Her hobbies, conveniently, mirror those of her 2-year-old: “jumping (why not?), dancing, exploring the world, lots of snacking, nap time.” Dr. Blackmon might also have a fallback career in the works. “If I wasn’t a hematologist, my dream would be to be on Broadway. It’s never too late.” True words.

Dr. Idoroenyi Amanam (@aMyeloidPersona) is based at City of Hope where he is an assistant professor of leukemia and hematopoietic cell transplantation, focusing on leukemia, stem cell transplantation, and myeloproliferative neoplasms. He is a triple-boarded physician with advanced fellowship training utilizing cellular and stem cell therapy to treat malignant conditions. He completed his hematology and oncology training at City of Hope, serving as chief fellow. He was then awarded the prestigious City of Hope Hematopoietic Cell Transplantation and Cellular Therapy Fellowship, with a concentration on acute leukemias and myeloproliferative neoplasms. Dr. Amanam was awarded a Congressional Award in voluntary public service, and he carries this spirit into the clinic. “I believe in treating all my patients with compassion and utilizing intellectual curiosity to tailor my treatment approaches,” he shared. He also believes he was chosen to enter this field as he had a loved one who struggled with cancer and lived years longer than expected thanks to compassionate care by the doctors and nurses.

The practical connection between inflammation and malignancies dates back to 1863 when German pathologist, Richard Virchow, identified white blood cells in cancerous tissue and proposed that cancer originates at sites of chronic inflammation. We now understand that certain myeloid malignancies may be derived from mutant, clonally derived stem cells with a competitive survival advantage in the setting of inflammation. Additional secondary mutations may then lead to progression of these malignancies. The intricacies and multifactorial etiology of myeloid diseases leave many questions still unanswered.

Drs. James P. Allison and Tasuku Honjo received the Nobel Prize in Physiology and Medicine for their work in cancer immunotherapy. The interplay between inflammation, immunity, malignant disease, and progression is a widely accepted concept in oncogenesis. However, the exact mechanisms that dictate the terms of this relationship remain elusive.

During the Scientific Committee Joint Session on Myeloid Biology and Neoplasia, “Seed and Soil: The Role of Inflammation in Myeloid Malignancies” (Saturday, December 10, 4:00 p.m.-5:30 p.m., Room R02-R05, Ernest N. Morial Convention Center), both cell-intrinsic and cell-extrinsic roles of inflammation in the pathogenesis of myeloid neoplasms will be explored. Is there a unifying mechanism that allows mutant hematopoietic stem cells to outcompete normal hematopoietic stem cells in an inflammatory environment? Dr. Katherine King, in her talk on “Inflammatory Signaling and Clonal Hematopoiesis,” will attempt to answer this. “There is so much interest in how inflammation and clonal hematopoiesis interact in a self-reinforcing loop,” she said in an interview with ASH News Daily. Dr. King’s talk will cover the mechanisms behind this, and she will also discuss her team’s work demonstrating mycobacterial infections driving the expansion of DNMT3A mutant pre-leukemic hematopoietic stem cells.

Multiple groups are evaluating the concept of chronic inflammation as a determinant of the competitiveness of hematopoietic stem cells and the development of leukemia. Dr. Christina Celso’s talk titled “Contribution of the Bone Marrow Microenvironment to Leukemogenesis” will take this idea a step further and evaluate the link between acute leukemia and its ability to respond to and thrive in an inflammatory state, in addition to therapeutic considerations. “We found that while acute inflammation reduces leukemia stemness, this rebounds later,” she stated in an interview. “This is a potential mechanism of resistance to immune responses and to many types of immunotherapy approaches, which will be important to target as immunotherapy of acute myeloid leukemia continues to remain challenging.”

We are still not completely clear on the molecular or metabolic basis for differential responses to inflammatory signaling. Dr. Eric Pietras will discuss the role that inflammatory signaling plays in the selection of mutant hematopoietic stem and progenitor cells during his talk titled “Dysregulated Inflammatory Signaling in the Pathogenesis of Myeloid Malignancies.” His presentation will offer unique insights into the metabolic features of mutant hematopoietic stem cells and will evaluate how inflammation triggers clonal expansion. He describes this as a “classic fire triangle in which each component — increased inflammation, altered metabolism and the underlying mutant genetic background — is part of an interdependent system.” He went on to say, “We believe this information can be helpful in understanding how myeloid malignancies evolve in the marrow and identifying rational approaches for early intervention in individuals at increased risk of developing disease.”

Finally, Dr. Daniel Sarczynowski will expand on the concepts presented during his talk titled “Therapeutic Implications of Inflammatory Signaling in Myeloid Malignancies.” He explained to ASH News Daily that in the past 10 years, significant progress has been made in our understanding of the contribution of innate immune pathways and inflammation to age-related hematopoietic malignancies. “Importantly, the field has reached a critical inflection point,” He stated, noting that the session will review and discuss the current state of evidence supporting the role of dysregulated innate immune signaling and inflammation that contribute to myeloid malignancies, and propose how emerging concepts will further reveal critical biology and novel therapeutic opportunities.

This Joint Session is an exciting window of opportunity to identify new targets within the inflammatory milleua that may lead to improved outcomes in a group of diseases difficult to extinguish.

Dr. Amanam and Dr. Blackmon indicated no relevant conflicts of interest. 

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