Blood: Single-cell omics reveals multilayered molecular mechanisms of CLL acquired venetox resistance

Venetox (VEN) induces apoptosis by inhibiting the anti-apoptotic protein BCL2 and is the standard treatment for chronic lymphocytic leukemia (CLL), providing patients with recurrent CLL with high complete response rates and longer progression-free survival, but ultimately loses efficacy
.
At present, the genetic changes of subclonal changes associated with VEN resistance have been well studied
.

To fully understand the mechanisms of clinical resistance in VEN, the researchers combined single-cell short-read and long-read RNA sequencing to reveal the previously unrecognized scale of
genetic and epigenetic changes supporting acquired VEN resistance.

Changes in survival signals in VEN resistant cells

The genetic and epigenetic changes in acquired VEN resistance appear to be multilayered
.
One layer includes changes in the Apoptotic regulator BCL2 family, particularly in former surviving family members
.
This includes previously described BCL2 mutations and amplification of the MCL1 gene, but is not uniform between individual leukemia patients and leukemia patients
.
With the exception of a single case of BAX or NOXA subclonal deletion, pro-apoptotic gene variants are significantly uncommon
.

Molecular mechanisms of VEN resistance

Notably, the expression of the MCL1 gene is generally upregulated
.
This is driven by an emergency NF-κB activated overburden; During VEN treatment, there is persistent activation of NF-κB in circulating cells
.
The researchers also found that MCL1 could be a direct transcriptional
target for NF-κB.
After deactivating VEN, switching to other pro-survival factors and NF-κB activation largely disappeared
.

In conclusion, the study reveals the degree of
plasticity of CLL cells in evading VEN-induced apoptosis.
Importantly, these findings clarify new ways to circumvent VEN resistance and provide a specific biological rationale for strategies to discontinue VEN once maximum response is achieved, rather than long-term selective pressure
to maintain drugs.

Original source:

Rachel Thijssen, Luyi Tian, Mary Ann Anderson, et al.
Single-cell multiomics reveal the scale of multilayered adaptations enabling CLL relapse during venetoclax therapy.
Blood (2022) 140 (20): 2127–2141.