Novel Drugs for Leukemia to emerge from targeting B CELL Development

B cell development stages

B cell development involves several stages, which can be summarized as follows:

• Early B cell development in the bone marrow: Hematopoietic stem cells differentiate into common lymphoid progenitors (CLPs), which further mature into B cell progenitors (also known as pro-B cells). These pro-B cells undergo rearrangement of their immunoglobulin (Ig) genes to generate a functional B cell receptor (BCR). This process involves rearranging Ig heavy chain genes (IgH) and the expression of a pre-BCR complex.
• Late B cell development in the bone marrow: Pro-B cells develop into pre-B cells, which express a functional pre-BCR on their surface. Successful rearrangement and expression of IgH genes lead to positive selection and further differentiation into immature B cells. These immature B cells express both IgM and IgD BCRs and undergo negative selection to remove self-reactive cells.
• B cell maturation in peripheral lymphoid organs: Mature B cells exit the bone marrow and migrate to secondary lymphoid organs, such as the spleen and lymph nodes. In these organs, mature B cells encounter antigens presented by dendritic cells or follicular dendritic cells. Upon antigen recognition and appropriate co-stimulation, mature B cells differentiate into either plasma cells or memory B cells.
• Differentiation into plasma cells or memory B cells: Antigen-activated B cells can differentiate into plasma cells, which produce and secrete large amounts of antibodies specific to the encountered antigen. Plasma cells are responsible for the humoral immune response. Alternatively, B cells can differentiate into memory B cells, which provide long-lasting immunity by quickly responding to subsequent encounters with the same antigen.

Role of BCL2 and Asparginase in B-ALL

Despite having an overall survival rate of 94%, B-cell acute lymphoblastic leukemia (B-ALL), the most common childhood cancer, can prove challenging to treat, with survival among relapsed or resistant cases falling between 30-50%.

B-ALL is a cancer derived from white blood cells called B cells. Under normal circumstances, B cells develop from immature to fully mature, passing through eight steps. In cancers, cells can get stuck in an intermediate stage of development. 

BCL2 and asparaginase play crucial roles in the context of B-cell acute lymphoblastic leukemia (B-ALL)

• BCL2 (B-cell lymphoma 2):BCL2 is a protein that plays a key role in regulating apoptosis, or programmed cell death. It acts as an anti-apoptotic protein, helping cells survive by preventing apoptosis.
• In B-ALL, dysregulation of BCL2 expression or function can occur, leading to increased survival of leukemic B cells. This dysregulation can be caused by genetic alterations or other factors.
• Targeting BCL2 has become an important therapeutic strategy in B-ALL. Drugs that inhibit BCL2, such as venetoclax, have shown efficacy in inducing apoptosis specifically in leukemic B cells, thereby helping to treat B-ALL.

• Asparaginase: Asparaginase is an enzyme that depletes circulating levels of the amino acid asparagine by converting it to aspartic acid and ammonia. Some leukemic cells, including B-ALL cells, are unable to synthesize asparagine and rely on circulating asparagine for survival and proliferation.
• By depleting asparagine, asparaginase selectively targets leukemic cells while sparing normal cells that can synthesize asparagine. This selective cytotoxicity makes asparaginase an effective chemotherapy agent in the treatment of B-ALL.
• Asparaginase is commonly used as part of combination chemotherapy regimens for B-ALL. It is often administered during the induction phase of treatment to rapidly reduce leukemic cell burden and achieve remission.

The  novel drug combination (Asparginase & Venetoclax )

 The team of scientists at  St. Jude Children's Research Hospital uncovered the resistance mechanisms of tumor cells to asparaginase, a commonly used drug for B-ALL, and the rationale behind its imprecise usage due to a lack of understanding of its mechanism of action. By combining asparaginase with venetoclax, a BCL-2 targeted therapy, the researchers observed enhanced effectiveness in controlling high-risk subtypes of B-ALL in laboratory models. This combination therapy reduced the number of leukemia cells more effectively and rapidly than either drug alone, offering the potential to lower the risk of ALL relapse, thereby addressing a major cause of treatment failure.

The study's significance lies in its utilization of single-cell systems biology analysis to identify the protein BCL-2 as a hidden vulnerability in the developmental stage of asparaginase-resistant tumor cells. By examining gene expression data from hundreds of thousands of individual cancerous B cells, the researchers identified two dominant B-cell development stages of B-ALL, pre-pro-B and pro-B, and found that the protein BCL-2 played a pivotal role in asparaginase resistance in leukemia cells with pre-pro-B features. This led to the hypothesis that asparaginase upregulates mTOR signaling, subsequently activating BCL-2 and increasing the cells' sensitivity to venetoclax. The study's implications extend beyond B-ALL, as the findings suggest that developmental arrest of cancer cells can make them sensitive to certain drugs, providing opportunities to identify new drug combinations to improve treatment outcomes.

In conclusion, the research presents a significant advancement in understanding the resistance mechanisms of B-cell acute lymphoblastic leukemia (B-ALL) and the rational design of a combination therapy using asparaginase and venetoclax. The study's use of single-cell systems biology analysis has not only identified a hidden vulnerability in the developmental stage of asparaginase-resistant tumor cells but also offers potential insights into improving therapies for other cancers with similar developmental arrest mechanisms.

This work paves the way for future clinical trials to further investigate the therapeutic potential of the drug combination in treating B-ALL, potentially addressing the major challenge of treatment failure due to relapse.

REFERENCES

https://medicalxpress.com/news/2024-04-vulnerability-cell-drug-combination-leukemia.html

https://www.cell.com/cancer-cell/fulltext/S1535-6108(24)00088-6