The Promise of Apela in Chronic Lymphocytic Leukemia
5-year survival for advanced CLL
Patients develop resistance to initial therapies
New targeted therapies in development
Year Apela-CLL connection discovered
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries, affecting thousands of people each year. This blood cancer occurs when the body produces too many abnormal B-lymphocytes, which gradually accumulate in the blood, bone marrow, and lymph nodes 2 6 . For decades, treatment has relied on chemotherapy and, more recently, targeted therapies that have significantly improved patient outcomes 3 4 .
Despite these advances, CLL remains incurable for most patients. Current treatments, including Bruton tyrosine kinase (BTK) inhibitors like ibrutinib and BCL-2 inhibitors like venetoclax, have transformed patient care but eventually face the challenge of resistance 4 . When leukemia cells develop resistance to both BTK inhibitors and BCL-2 inhibitors—a scenario clinicians term "double-refractory" CLL—treatment options become severely limited, and the prognosis worsens significantly 3 4 .
This pressing medical need has driven scientists to search for novel therapeutic targets, leading them to investigate fundamental biological processes like programmed cell death (apoptosis). In healthy bodies, apoptosis eliminates damaged or unnecessary cells, but cancer cells notoriously evade this self-destruct mechanism 1 9 . Recent research has illuminated a surprising player in this process—a tiny peptide called Apela (also known as ELABELA)—that might hold the key to new CLL treatments 1 .
Discovered relatively recently, Apela is a small secretory peptide that acts as a signaling molecule in the body. It's encoded by the APELA gene located on chromosome 4 in humans and exists in several forms, including the mature 32-amino acid peptide called ELABELA-32 9 .
Along with its relative apelin, Apela binds to a receptor called APJ on cell surfaces, forming what scientists term the "apelinergic system" 9 .
Apela's potential relevance to cancer lies in its ability to influence apoptosis. Research has shown that Apela can inhibit programmed cell death by activating specific signaling pathways within cells, particularly the PI3K/AKT pathway, which promotes cell survival 9 . Under normal circumstances, this function helps maintain healthy tissues, but cancer cells may exploit this survival signal to their advantage.
In CLL, the malignant B-cells already display high levels of anti-apoptotic proteins like Bcl-2, Bcl-XL, and Mcl-1, which contribute to their abnormal longevity 1 . The discovery that Apela further inhibits apoptosis suggested it might play a role in CLL pathology and represent a new therapeutic opportunity.
In 2019, a team of researchers proposed a compelling hypothesis: if Apela inhibits apoptosis and CLL cells resist cell death, then perhaps Apela levels are elevated in CLL patients. Furthermore, they speculated that targeting Apela might represent a novel therapeutic strategy for this common leukemia 1 .
They enrolled 42 untreated CLL patients and 41 healthy volunteers to serve as controls.
Blood samples were collected from all participants.
The blood samples were processed to separate serum, the liquid component of blood that contains circulating proteins and peptides.
Serum Apela levels were measured using enzyme-linked immunosorbent assay (ELISA) kits, which can detect and quantify specific proteins with high sensitivity.
The Apela levels between CLL patients and healthy controls were compared using appropriate statistical methods, and correlations with CLL disease characteristics were explored 1 .
The study yielded clear and compelling results:
| Group | Number of Participants | Serum Apela Levels | Statistical Significance |
|---|---|---|---|
| CLL Patients | 42 | Significantly Higher | p < 0.05 |
| Healthy Controls | 41 | Lower | Reference group |
The data demonstrated that CLL patients had significantly elevated levels of circulating Apela compared to healthy individuals 1 . This finding represented the first direct evidence linking Apela to CLL in humans.
The elevated Apela levels in CLL patients suggest several important possibilities:
Apela may contribute to the disease by enhancing the survival of malignant B-cells
Apela could be a biomarker for disease presence or activity
Targeting the Apela-APJ pathway might therapeutically restore apoptosis in CLL cells
The researchers concluded that "ELA targeting may be a potential therapeutic option for treating CLL" 1 , drawing attention to this previously overlooked molecule as worthy of further investigation in targeted cancer therapy.
Investigating Apela's role in CLL requires specialized reagents and methodologies. Here are the key tools enabling this research:
| Tool/Method | Function/Application | Example from Research |
|---|---|---|
| ELISA Kits | Measure Apela peptide levels in biological samples like blood serum | Used to compare Apela levels in CLL patients vs. healthy controls 1 |
| Animal Models | Study Apela function in living organisms; test potential therapies | Zebrafish models show Apela's role in blood vessel formation 7 |
| Flow Cytometry | Analyze cell surface markers and classify lymphocyte populations | Essential for CLL diagnosis (detects CD5+, CD19+, CD23+ B-cells) 2 |
| Morpholino Oligos | Temporarily block gene expression to study function | Apela morpholinos inhibited blood vessel remodeling in zebrafish 7 |
| Signal Transduction Assays | Map cellular pathways activated by Apela-APJ binding | Identified PI3K/AKT as key pathway activated by Apela 9 |
These tools have been instrumental in establishing our current understanding of Apela's biology and its potential role in CLL. As research progresses, additional tools like Apela-specific antibodies for tissue staining, recombinant Apela proteins for functional studies, and small molecule inhibitors of the Apela-APJ pathway will become increasingly important.
Monoclonal antibodies that bind to and neutralize Apela, preventing it from activating its receptor and sending survival signals to cancer cells.
Small molecules that occupy the APJ receptor without activating it, serving as competitive antagonists to Apela.
Apela-targeting agents could be combined with existing BTK or BCL-2 inhibitors to overcome resistance or enhance efficacy.
Apela levels might help identify patients who would benefit most from specific treatments or monitor treatment response.
Answering these questions will require extensive preclinical studies and clinical trials before Apela-targeted therapies might become available to patients.
The discovery of elevated Apela levels in CLL patients represents an exciting development in the ongoing quest to conquer this common leukemia. As a regulator of apoptosis—the fundamental process that cancer cells evade—Apela represents a biologically plausible target for novel therapeutics 1 9 .
While current targeted therapies like BTK and BCL-2 inhibitors have revolutionized CLL treatment, the emerging problem of double-refractory disease underscores the need for continued innovation 3 4 . Apela-directed therapy could potentially address this unmet medical need, either as a standalone treatment or as part of combination strategies.
As research progresses, the scientific community watches with anticipation to see whether this tiny peptide will fulfill its promise and become the next big breakthrough in leukemia treatment. For the thousands of patients living with CLL, each new potential target like Apela represents hope for more effective and durable treatments in the future.
The field of CLL research continues to evolve at a remarkable pace. As one expert recently noted, "The current landscape of CLL is diverse, following improvements in treatment in the last decade," with both continuous and fixed-duration therapies now being explored . In this context, novel targets like Apela may provide the key to further advancing patient care.