T-cell acute lymphoblastic leukemia (T-ALL) is a specific form of acute lymphoblastic leukemia, the most common cancer in childhood. It is an aggressive tumor affecting white blood cells of the immune system called T-lymphocytes. While in normal conditions T-lymphocytes are essential players of the immune response to infections, in T-ALL these cells do not mature properly and are functionally impaired. The malignant transformation of T-cells results in their uncontrolled proliferation and infiltration of several organs throughout the body, including the bone marrow, the spleen, and the central nervous system.
Thanks to current therapeutic protocols (chemotherapeutic drugs and corticosteroids), cure rates reach 80% for pediatric and 60% for adult patients. Nevertheless, a considerable fraction of patients faces poor prognosis because of resistance to treatments or secondary relapse of the disease. For these patients, more effective and less toxic therapies are needed. To achieve this, scientists are working to more accurately characterize the molecular mechanisms of T-ALL and to discover new targets for more specific and tailored therapies.
The pathologic process leading to the transformation of a normal developing T-cell into its tumoral counterpart is driven by multiple genetic mutations which activate several signaling pathways. Signaling pathways are “molecular relay races” of proteins that interpret and integrate the information delivered by different chemical signals. These molecular cascades eventually induce a change in gene expression, thus producing a functional response inside the cells. However, while in healthy cells signaling pathways are finely controlled and tuned, in T-ALL this accurate regulation is lost, and several cell functions, including growth, proliferation, differentiation, and survival, are impaired.
Though many of the changes resulting in T-ALL transformation come from the cell itself, the microenvironment surrounding the tumor also can activate specific signaling pathways that dictate tumor behaviour. The microenvironment can feed tumor cells extracellular cues such as growth factors and other signaling molecules, allowing the establishment of a complex interplay between cancer cells and their neighborhood. Oxygen and nutrient availability, also part of the microenvironment, can impact cancer metabolism. These factors, together with the heightened demand for metabolites and the abnormal function of metabolic sensors and regulators, drive T-ALL cells towards aberrant behavior.
Altogether, these features make T-ALL cells unique from normal T-lymphocytes and thus the subject of intense research, opening the path for the design of new drugs.
Moreover, signaling pathways are strictly connected inside the cell and can crosstalk in tangled networks. Therefore, targeting a few but specific components of distinct pathways in combination would hopefully be sufficient to induce a broad and effective anti-tumoral effect. The genetic and molecular landscape of T-ALL is intricate and still not completely explored, but research is progressively providing us with the tools to build a compass to find our way through.
Research article: Aberrant Signaling Pathways in T-Cell Acute Lymphoblastic Leukemia. International Journal of Molecular Sciences. 2017.