Project Goal:

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.

Project Update 2024:

Acute myeloid leukemia (AML) is the second most common type of blood-forming cancer among children. Despite novel therapeutics advancements, at least 1 in 5 children still suffer from incomplete cancer cell elimination and relapse. Recent research shows evidence that inflammation in the bone marrow (BM) is a significant factor in driving leukemic persistence, but the underlying biology that sustains inflammation in patients’ BM microenvironment remains not well understood. Our studies to date have shed light on the involvement of HSPC hematopoietic stem and progenitor cells (HSPCs), traditionally known as bystanders in AML pathogenesis, plays a contributing role in the AML microenvironment. Utilizing two mouse AML models, we show that: 1)HSPC exhibit inflammatory signaling in both AML microenvironment; 2) AML cells can secrete nanometer-sized signaling molecules, known as extracellular vesicles (EVAML), to incite inflammation in HSPCs. More recently, we demonstrated using human models that human AML cancer cells can also secrete these nanometer-sized signaling molecules and trigger inflammation in human BM HSPCs. Experiments are currently underway to understand whether these inflammatory insult on HSPCs imprint long-term memory in these cells that may change how they respond to future stressors. Understanding how AML reconfigures the HSPCs to fuel relapse has broad applicability independent of AML subtypes and enables us to generate new scientific knowledge that can help with the development of new treatment approaches aimed at impeding relapse.