Distinct molecular profiles lead to a better understanding of acute leukemia

The complex and diverse nature of the genetic alterations driving acute leukemia can make these diseases challenging to treat. Acute leukemia is a fast-developing type of cancer that originates in blood-forming tissues such as bone marrow, leading to an overproduction of immature white blood cells, called blasts. Acute leukemia is the most common form of childhood cancer, and its occurrence is on the rise.

Despite constituting only 20% of pediatric acute leukemia, acute myeloid leukemia (AML) is emerging as the leading cause of mortality among childhood leukemia cases. This is partly due to the aggressive nature of AML but also due to gaps in understanding the genomic underpinnings of the disease and how genes are expressed and regulated in AML cells. 

A gene fusion called PICALM::MLLT10 (PM) is a rare but recurring genetic driver associated with different subtypes of acute leukemia. Although PM-positive AML is uncommon and accounts for less than 1% of pediatric AML cases, understanding why AML patients with PM fusion have particularly poor outcomes is instrumental to understanding AML.

By exploring and contrasting the genetic and transcriptomic profiles of AML and T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LLy) with PM fusions, St. Jude scientists have uncovered new insights about the unique molecular signatures of each subtype. This knowledge could pave the way for targeted therapy and improve outcomes for these challenging-to-treat forms of leukemia.

Unique genetic signatures differentiate AML and T-ALL/LLy among acute leukemia

Previous work to understand PM fusions in acute leukemia was done in T-ALL/LLy, which is more common than PM-AML but still considered rare. Lu Wang, MD, PhD, St. Jude Department of Pathology, and her team investigated the molecular characteristics unique to each subtype of leukemia with the PM fusion, aiming to provide valuable insights for future research and treatment. Their findings were published recently in Leukemia.

Their investigation relied on a cohort of 20 patients, spanning various lineages of leukemia, but primarily including AML and T-ALL/LLy, as well as a few rarer conditions, such as mixed-phenotype acute leukemia and acute undifferentiated leukemia. “In our study, we focused on understanding the genomic makeup of PM-positive acute leukemias, a group of patients underrepresented in research studies due to the rarity of their condition,” Wang explained.   

Their study found that the 20 leukemia cases could be placed into two groups based on global gene expression analysis, with PM-AML cases falling into one group and PM–T-ALL/LLy cases falling into another, confirming that these two forms of leukemia have distinct molecular characteristics. Despite the differences, both groups showed elevated expression of specific HOXA genes and XPO1, suggesting shared traits. Functional classification of the genes revealed that cell proliferation-related pathways, such as the G2M checkpoint and E2F targets, were enriched in all subgroups, indicating that the cancerous cells were actively dividing.

“Our goal was to explore the genetic and transcriptomic profiles of these patients to identify subtype-specific molecular signatures that could offer insights into disease progression and potential therapeutic targets,” added co-author Rebecca Voss, MD, lead researcher, Department of Pathology. The researchers meticulously analyzed genomic and transcriptomic profiles in these patients, aiming to uncover subtype-specific molecular signatures and potential therapeutic targets.

AML and TP53 mutations: A key factor in disease relapse and progression

“The most compelling finding from our study was that patients with AML with this fusion typically have cooperating mutations in the TP53 gene, which you don’t particularly see in T-ALL cases,” said Jeffery Klco, MD, PhD, St. Jude Department of Pathology, and co-author on the study. 

TP53 is a tumor suppressor gene critical in regulating cell growth and preventing cancer. Mutations in this gene can lead to uncontrolled cell proliferation and cancer development.

Genomic characterization revealed distinct transcriptomic profiles between PM-AML and PM–T-ALL/LLy, with different scales of co-occurring mutations. Researchers observed a high frequency of gene alterations, such as TP53 and NF1 — genes encoding for proteins that help regulate cell growth among PM-AML patients. These alterations often lead to a loss of function in these genes, which can play a role in cancer development and progression. 

“We see this trend that they are occurring in AML rather than T-ALL/LLy. Not just that, but also that the frequency at which they occur in AML is much higher than what has been reported for pediatric AML,” Voss stated.  

“It has been known that patients with PM-AML have a poor outcome compared to other AML subtypes. And I think this study provides some rationale for why that happens, why those children unfortunately have such outcomes, and it’s these TP53 mutations,” expressed Klco.

These findings underscored the clinical significance of these findings, providing a rationale for the poor prognosis in affected patients and laying the groundwork for future targeted therapeutic interventions.

PHF6 discovery challenges AML assumptions

Additionally, investigators found that PHF6 was the most frequently mutated gene in both PM-AML and PM–T-ALL/LLy, affecting 12 patients. PHF6 is a transcriptional regulator, and its disruption is a key cooperating event in PM-positive leukemia, particularly PM-AML. The finding is unexpected and challenges conventional assumptions about the role of PHF6 in leukemia.

“PHF6 alteration is commonly associated with T-ALL, so finding a high frequency of PHF6 alterations in AML cases was quite surprising. It suggests a unique molecular landscape in PM- AML and highlights the need for further investigation,” Wang said. Wang and her team uncovered additional differences in gene expression profiles and co-occurring mutations between PM-AML and PM–T-ALL/LLy, offering valuable insights into the distinct molecular characteristics of these subtypes and their potential implications for diagnosis and treatment.

Looking ahead, the researchers are optimistic about the future implications of their work. Ongoing efforts to validate their findings in larger patient cohorts and explore targeted therapeutic interventions, such as Menin inhibitors and SINEs targeting XPO1, hold promise for improving outcomes for individuals with these rare and challenging forms of leukemia.

“Investigating rare diseases like PM-positive leukemias presents unique challenges, but it also offers immense opportunities for discovery and innovation in the field of pediatric oncology,” Wang said. “Our study represents a crucial step forward in understanding the molecular tumorigenesis of PM-positive acute leukemias and advancing personalized treatment strategies for affected patients.”