A cell out of tune: Tracing the earliest signs of leukemia risk

Before an orchestra performs, there is a moment the audience rarely considers: the tuning. One by one, instruments sound a note, and musicians listen for the smallest deviation from true pitch. The goal is harmony, but when a string plays slightly sharp or flat, it does not ruin the entire performance, as long as it is caught before the music starts.

Blood cells can be slightly “out of tune” too, and researchers at St. Jude are learning to recognize it. Long before a child is diagnosed with leukemia, the cells that will eventually become cancerous often pass through a subtly altered state: one that is not yet disease, but also not quite right. Scientists call this cellular state pre-leukemic, and understanding pre-leukemic cells and the disorders that arise from them is a promising frontier in pediatric cancer research. 

What makes one note drift and another hold steady

Not every instrument that drifts stays that way; some return to true pitch on their own. The same is true for cells.

“A leukemia typically involves an increase in blasts, which are immature cells that have characteristic features, along with an aggressive clinical course,” explains Jeffery Klco, MD, PhD, Division of Hematopathology & Molecular Diagnostics director within the Department of Pathology. “Before that happens, hematopoietic cells can undergo a series of changes within their genome and epigenome that alter key pathways to push them closer to a leukemia.”

Progression to disease can come from changes within individual cells, such as the emergence of genetically distinct subclones that carry a growth or survival advantage over their neighbors or a genetically predisposed hematopoietic system, or from outside of cells, such as from bone marrow inflammation. Genomic sequencing, led by Klco and colleagues, has mapped many of the later steps in that drift, sorting pediatric acute myeloid leukemia (AML) into more than twenty distinct molecular subtypes. 

Studying that earlier, quieter state matters because it provides insights that post-diagnosis research cannot offer. “If we can better understand the different ways that a pre-leukemia can progress to leukemia, we will be armed with options for therapeutic intervention,” Klco says. “Our collective goal is to block the development of an aggressive leukemia and to intervene when patients are more stable.” 

Klco’s earlier work hints at what that kind of intervention could look like. In adults with AML, Klco found that patients whose mutations cleared completely after initial chemotherapy were less likely to relapse than those with residual mutations, suggesting that tracking a cell’s molecular signature over time, not just how it looks under a microscope, could help guide intervention. The next step, according to Klco, is to “clinically test therapeutic interventions to determine if we can disrupt progression to leukemia in patients with a genetic predisposition.”

When the instrument corrects itself 

John Crispino, PhD, MBA, Division of Experimental Hematology director in the Department of Hematology, studies a pre-leukemic condition called transient abnormal myelopoiesis (TAM), which develops in roughly 5%-10% of newborns with Down syndrome, due to a mutation in a gene called GATA1. “TAM resolves spontaneously in the majority of cases without any treatment,” Crispino says. Related conditions, such as myelodysplastic syndrome, follow a similarly unhurried timeline. Some take years to transform, if they transform at all.

Progression to leukemia in children with Down syndrome is thought to require a sequence of genetic hits: trisomy 21, then a GATA1 mutation, then one or more additional driver mutations that push a stable clone into full-blown leukemia. Researchers are interested in understanding what factors promote that third genetic hit, driving cells to develop leukemia.  

One cue is quantity. Newborns with a larger burden of GATA1-mutant cells at birth appear more likely to progress to disease, simply because there are more cells in which a further mutation could occur. Inflammation may matter too, since Down syndrome is associated with inflammation and hyperactive interferon signaling; pathways Crispino suspects may help abnormal cells expand and persist long enough to acquire that next genetic hit. 

Crispino’s lab has also identified what can make that drift harder to reverse. Studying myeloproliferative neoplasms, a related group of blood disorders, in their most advanced, leukemia-like phase, Crispino and collaborators found a small region of chromosome 21 amplified (present in extra copies) in about a quarter of the cases they examined. The gene responsible, DYRK1A, had already been implicated separately in leukemia progression in children with Down syndrome, who carry an extra copy of that same chromosome from birth, a discovery that traces back to Crispino’s own lab more than a decade earlier. It is one extra note, playing too loudly, in more than one condition. 

Trying to quiet the drift 

Knowing a cell is out of tune does not automatically reveal how to fix it. In Germany, the multicenter TMD Prevention 2007 trial treated infants with symptomatic or higher-risk TAM with low-dose cytarabine, a widely used chemotherapy drug, testing whether early chemotherapy could prevent progression to leukemia. The treatment reduced early mortality, but it did not prevent leukemic progression. As Crispino puts it, the intuitive assumption that clearing the abnormal blasts early would stop leukemia from developing may not hold up in practice; the biology involved is more complicated than that. 

That difficulty has not stopped the search for gentler answers. Researchers are still working to determine whether a safe, nontoxic drug could halt progression in other pre-leukemic states. They are also trying to determine if every deviation warrants treatment or if clinicians should only treat the ones headed toward real dissonance. 

Across hematology laboratories at St. Jude, that search is still underway: one mutation, one signaling pathway, one small clue at a time. Klco and Crispino are, in effect, building the same instrument from different ends. One mapping how a note drifts once it has already begun to fall out of place; the other studying why some drift back into place on their own. Together, their body of work moves toward something neither could reach alone: a way to hear the earliest sign of trouble in a child's blood and identify the tools to correct it — before the child ever knows a note was out of tune at all.