Pediatric precursor B acute lymphoblastic leukemia: are T helper cells the missing link in the infectious etiology theory?

Abstract

Precursor B acute lymphoblastic leukemia (BCP-ALL), the most common childhood malignancy, arises from an expansion of malignant B cell precursors in the bone marrow. Epidemiological studies suggest that infections or immune responses to infections may promote such an expansion and thus BCP-ALL development. Nevertheless, a specific pathogen responsible for this process has not been identified. BCP-ALL cells critically depend on interactions with the bone marrow microenvironment. The bone marrow is also home to memory T helper (Th) cells that have previously expanded during an immune response in the periphery. In secondary lymphoid organs, Th cells can interact with malignant cells of mature B cell origin, while such interactions between Th cells and malignant immature B cell in the bone marrow have not been described yet. Nevertheless, literature supports a model where Th cells—expanded during an infection in early childhood—migrate to the bone marrow and support BCP-ALL cells as they support normal B cells. Further research is required to mechanistically confirm this model and to elucidate the interaction pathways between leukemia cells and cells of the tumor microenvironment. As benefit, targeting these interactions could be included in current treatment regimens to increase therapeutic efficiency and to reduce relapses.

Insights into the prenatal origin of childhood acute lymphoblastic leukemia

“…The exact mechanisms of leukemic transformation through infection are not yet fully understood, but dysregulation of the immune system may play a major role. It has been proposed that memory T helper cells can support preleukemic B cell precursors in the bone marrow, and thus support ALL development [26].…”

“…Recent studies have shown that exposure to infection can trigger the progression from preleukemia to ALL [24,25]. A dysregulated immune response by activation of preleukemic B cells through memory T helper cells [26] and inactivity of NK cells have also been discussed [27][28][29].…”

The Bone Marrow Niche in B-Cell Acute Lymphoblastic Leukemia: The Role of Microenvironment from Pre-Leukemia to Overt Leukemia

“…In addition to stromal cells, the immune microenvironment may also play an important role in the transition from pre-leukemia to leukemia. In particular, it has been proposed that memory T helper cells can support pre-leukemic BCP [ 54 ] and that Natural Killer (NK) cells with a low killing efficiency can confer a higher risk of ALL development by failing to clear pre-leukemic cells and early leukemic progenitors [ 5 , 55 ].…”

The Role of MicroRNA in Paediatric Acute Lymphoblastic Leukaemia: Challenges for Diagnosis and Therapy

“…High levels of IL-6 are thought to play a role in expression of let-7a [83]. In accord with the “Greaves hypothesis” of an infectious origin for BCP-ALL [82], Bürgler and Nadal [84] suggest that memory T-helper (Th) cells may be attracted by preleukaemic B-cells and can then be activated through presentation of antigens. BCP-ALL cells can also respond to Th cell cytokines [84].…”

“…In accord with the “Greaves hypothesis” of an infectious origin for BCP-ALL [82], Bürgler and Nadal [84] suggest that memory T-helper (Th) cells may be attracted by preleukaemic B-cells and can then be activated through presentation of antigens. BCP-ALL cells can also respond to Th cell cytokines [84]. Correspondingly, miRNA have been shown to play a role in the regulation of cytokine genes and to be strongly regulated themselves during inflammation.…”