Hematopoietic Stem And Progenitor Cells Sustain Inflammation And Promote Relapse In The AML Niche
Children's Hospital of Philadelphia
Ding-Wen (Roger) Chen, PhD
Young Investigator Grants
Type of Childhood Cancer:
Acute Myeloid Leukemia (AML)
Acute myeloid leukemia (AML) is a type of cancer that arises from genetic changes in blood-forming cells in the bone marrow (BM). AML is the second most common type of blood-forming cancer among children. While recent therapeutic advancements have improved the overall survival of children with AML, at least 20% of children still suffer from incomplete cancer cell elimination and cancer recurrence (relapse). Moreover, children with AML relapse have a survival rate of less than 40%, making it a lead cause of fatal outcome in childhood cancer. In hopes to better understand relapse, research in the field has long focused on understanding the intrinsic genetic changes in leukemia cells that lead to persistence and progression. However, recent studies now suggest that the BM microenvironment can serve as a leukemia cell sanctuary, producing extrinsic factors that promote the growth of resistant leukemia cells. More recently, it has become clear that cells in the BM microenvironment play an important enabling role in relapse. Importantly, that observation is not limited to any single subtype of AML, but instead appears to apply broadly. While those mechanisms are emerging, inflammation appears to play an important role in reinforcing leukemia resistance.
Recent research shows evidence that inflammation in the bone marrow (BM) is a significant factor in driving leukemia recurrence. However, it is not well understood what sustains the inflammation process in patients’ BM microenvironment. My recent findings using a mouse model of acute myeloid leukemia (AML) show that leukemia cells initially engage healthy blood-forming stem cells to incite inflammation in the BM, in part through cell-cell crosstalk via nanometer size vesicles (EV-AML) released by the leukemia. More importantly, my studies simulating relapse in the AML mouse model show that healthy hematopoietic cells from mice that experienced AML actually promote a more aggressive secondary disease, i.e. relapse. This leads to my hypothesis that AML trains hematopoietic cells to exert inflammatory cues, in turn helping leukemic cells to maintain a long-lasting inflammatory state that favors leukemia recurrence. Understanding how AML reconfigures the BM to fuel relapse has broad applicability independent of AML subtypes, and enables us to generate scientific knowledge to develop new treatment approaches aimed at relapse. In this project, I propose three aims to rigorously test this hypothesis: 1) I will determine the signaling molecules that leukemia cells release to trigger inflammation in hematopoietic cells in AML. 2) I will investigate whether inflammatory cues released by hematopoietic cells can directly support the growth and survival of leukemia cells. 3) I will investigate whether hematopoietic cells that experienced AML can secrete amplified inflammatory cues and promote leukemia cell recurrence. My long-term goal is to improve survival of children diagnosed with AML. Understanding how AML reconfigures the BM to fuel relapse has broad applicability across disease subtypes, and generates new scientific knowledge that can lead to new treatment approaches aimed at the key regulators of relapse.