In the intricate world of cancer, sometimes the most dangerous players are not the obvious villains, but the trusted allies that protect them.
Imagine a security guard, entrusted with protecting a building, who suddenly switches allegiance and begins shielding a dangerous criminal inside. In an aggressive form of leukemia, a protein called USP7 does exactly this. Instead of performing its normal cellular duties, it becomes a "bodyguard" for a cancer-causing protein called NOTCH1, directly fueling the disease's progression. This discovery is now opening up exciting new possibilities for cancer treatment that were unimaginable just a few years ago.
USP7 stabilizes NOTCH1 by removing ubiquitin tags, preventing its degradation in T-ALL cells.
USP7 inhibitors show promise as an indirect way to target the "undruggable" NOTCH1 pathway.
To understand why the relationship between USP7 and NOTCH1 is so significant, we must first look at the NOTCH1 signaling pathway—an ancient communication system that governs fundamental cellular processes like growth, division, and specialization. Think of it as a molecular voting system where cells communicate with their neighbors to determine their fates.
NOTCH1 receives external signals
Controlled activation of target genes
Proper cell differentiation and growth
NOTCH1 hyperactive (stuck "on")
Uncontrolled gene expression
Excessive T-cell proliferation
"Given its central role, NOTCH1 has been an obvious target for therapy. However, directly inhibiting it has proven challenging in the clinic because the same protein is essential for many normal physiological processes, leading to severe side effects5 ."
Enter USP7 (Ubiquitin-Specific Protease 7), a deubiquitinating enzyme that acts like a master regulator of protein stability within our cells2 7 .
In T-ALL, USP7 undergoes a dangerous role reversal. Research has revealed that USP7 is significantly upregulated in human T-ALL cell lines and patient samples1 .
The process works like this1 5 :
NOTCH1, particularly its active intracellular domain (ICN1), becomes prone to being tagged with ubiquitin chains, marking it for destruction.
USP7 directly binds to NOTCH1, with its MATH and UBL domains being crucial for this interaction.
Once bound, USP7 uses its enzymatic activity to strip off the ubiquitin chains.
This deubiquitination stabilizes NOTCH1, allowing it to accumulate to higher levels and continue driving the expression of pro-growth and pro-survival genes in the nucleus.
This partnership creates a vicious cycle: NOTCH1 activation actually promotes the expression of USP7, which in turn stabilizes NOTCH1, creating a powerful feed-forward loop that fuels leukemia progression5 .
How did scientists uncover this critical relationship? A landmark 2018 study published in Signal Transduction and Targeted Therapy provided compelling evidence through a series of meticulous experiments1 .
First, the team confirmed that USP7 and NOTCH1 proteins physically interact in T-ALL cells. Using immunoprecipitation, they showed direct binding via MATH and UBL domains1 .
They manipulated USP7 levels and observed effects: USP7 knockdown decreased NOTCH1 levels, while USP7 overexpression increased them1 .
USP7 inhibition suppressed T-ALL cell proliferation and induced apoptosis. Animal models showed tumor growth suppression with USP7 depletion1 .
| Experimental Manipulation | Effect on NOTCH1 Protein Level | Effect on NOTCH1 Ubiquitination | Biological Outcome |
|---|---|---|---|
| USP7 Knockdown | Decreased | Increased | Suppressed T-ALL cell growth |
| USP7 Overexpression | Increased | Decreased | Enhanced NOTCH1 signaling |
| USP7 Pharmacological Inhibition | Decreased | Increased | T-ALL cell death (apoptosis) |
Uncovering the USP7-NOTCH1 axis required a sophisticated array of research tools1 :
The discovery that USP7 stabilizes NOTCH1 has transformed our understanding of T-ALL biology and opened new therapeutic avenues. The most exciting implication is that inhibiting USP7 could be a viable strategy to indirectly target the "undruggable" NOTCH1.
Small molecule inhibitors (P22077, OAT-4828) block USP7 enzymatic activity.
Without USP7 protection, NOTCH1 gets tagged with ubiquitin chains.
Ubiquitinated NOTCH1 is recognized and destroyed by the proteasome.
Reduced NOTCH1 signaling leads to apoptosis of leukemia cells.
Several USP7 inhibitors have now been developed and show promising anti-leukemic effects in preclinical models. The beauty of this approach is that it may offer a way to disrupt the oncogenic NOTCH1 signaling network with fewer side effects than direct NOTCH1 inhibitors.
However, the story has recently grown more complex. A 2025 clinical study revealed that USP7 mutations in pediatric T-ALL patients are associated with adverse outcomes.
This suggests that the role of USP7 in leukemia might be context-dependent, potentially acting as both an oncogene and a tumor suppressor in different scenarios. This paradox underscores the complexity of cancer biology and the need for personalized therapeutic approaches.
The story of USP7 and NOTCH1 in T-ALL is a powerful example of how basic scientific research can reveal unexpected vulnerabilities in cancer. By identifying USP7 as a critical stabilizer of the NOTCH1 oncoprotein, researchers have not only advanced our fundamental understanding of leukemia but have also paved the way for a novel therapeutic strategy.