Gimme fuel, gimme fire
Gimme that which I desire
Metallica – “Fuel”
As we gear up for the information-packed days of #ASH24, our mitochondria will be working overtime to fuel our minds to navigate the rapidly evolving clinical and scientific data — and our legs, for those inevitable sprints between distant sessions.
The Scientific Workshop Mitochondria and Metabolism in Blood Cancer – From Discovery to Patients will showcase how energy-generating processes are co-opted in hematological malignancies. ASH attendees will be familiar with the essential role mitochondria play in intrinsic apoptosis, regulated by the BCL-2 protein family that control the trigger switch for mitochondrial membrane permeabilization — the point of no return for cell death. The blockbuster success of BCL-2 inhibitors, the first mitochondrial-targeted therapies in blood cancers (and featured in more than 400 abstracts this year), underscores the immense potential of targeting intrinsic cellular mechanisms. This workshop, which brings together a diverse lineup of speakers comprising clinicians and basic and physician-scientists, will spotlight emerging therapies targeting metabolism and mitochondria.
“Our goal is to bring together a scientific community interested in mitochondria and metabolism in blood cancer, to foster discussion and collaboration,” said workshop co-chair Aaron D. Schimmer, MD. “With sessions covering discovery science, translational research, and clinical applications, we plan to illustrate how fundamental discoveries can inspire new treatments."
Targeting fundamental processes like cellular energy or oxidative phosphorylation (OXPHOS) in a cancer-specific manner remains a challenge. For instance, despite promising preclinical results in disrupting the cellular energy production of malignant cells dependent on OXPHOS, the investigational small molecule complex I inhibitor IACS-010759 has failed to progress beyond phase I trials due to toxicity. Yet these key malignant metabolic pathways harbor intrinsic vulnerabilities that can be manipulated, providing unique therapeutic opportunities for patients with challenging disease scenarios.
“We’ll also address targeting mitochondrial metabolism in leukemic stem cells, which are believed to be a critical disease reservoir,” said workshop co-chair Marina Konopleva, MD, PhD.
In healthy hematopoiesis, dormant hematopoietic stem cells (HSCs) rely on glycolysis, minimizing OXPHOS to protect against reactive oxygen species (ROS). Upon differentiation, HSCs shift to upregulate OXPHOS. In contrast, leukemic stem cells remain quiescent but rewire their energy metabolism to enhance OXPHOS. Exploiting this potential therapeutic vulnerability will be the focus of another workshop, Targeting Oxidative Phosphorylation for Pediatric Blood Cancer – From the Lab to the Clinic, led by Kathleen M. Sakamoto, MD, PhD.
The theme of metabolic dependencies will be further explored during the Scientific Program session Leveraging Single Cell Multi-Omics to Understand Mechanisms of Myeloid Lineage Expansion in Aging and Disease, with a focus on inflammation as a driver of aberrant myelopoiesis. Inflammatory signals are critical regulators of HSC development and maintenance, triggering differentiation, HSC exhaustion, and functional decline. The concept of "inflammaging," the chronic, low-grade elevation of markers of inflammation such as interleukin-6 and C-reactive protein seen in human aging, is implicated in a wide array of diseases, including cardiovascular and kidney disease, depression, and cancer. The HSC-derived phenomenon of clonal hematopoiesis, a hallmark of aging, lies squarely at the crossroads of aging and inflammation, with the intricate interplay among these factors serving as the central theme of this session.
Session speaker Elisa Laurenti, PhD, will discuss how the most common clonal hematopoiesis (CH) mutation, DNMT3A R882, impacts myeloid differentiation. “We have found that DNMT3A R882 drives a self-perpetuating inflammatory feedback loop, promoting relentless inflammation, with neutrophils playing a central role in the vicious cycle fueling malignant transformation,” Dr. Laurenti said.
During the same session, John E. Dick, PhD, will elaborate on how inflammation drives a newly described HSC population and reprograms the bone marrow niche. “We have recently found that an [HSC inflammatory memory (HSC-iM)] subset transmits its inflammatory signature and pro-inflammatory characteristics to myeloid progeny, perpetuating the inflammatory state,” said Dr. Dick. “HSC-iM arise from repeated inflammation but show increased dormancy and impaired differentiation as an adaptation. CH mutations relieve this state, conferring a selective advantage.”
Lastly, Allon Moshe Klein, PhD, will discuss state-of-the-art lineage tracing approaches in a large cohort of bone marrow biopsies, as well as the impact of the inflamed microenvironment on cell state.
Defining the intricate relationships between inflammation and metabolism in shaping HSC biology and driving hematologic malignancy opens new pathways for therapeutic exploration — and promises to fuel the next generation of breakthroughs in blood cancer treatment. As we power through #ASH24, remember this: Just like our mitochondria, we’re all in it to generate maximum output. (But don’t forget to charge your own batteries with your co-factor of choice — coffee, some San Diego sunshine, or an ASH pretzel at one of the meeting’s Poster Sessions!)
