In Utero Development and Immunosurveillance of B Cell Acute Lymphoblastic Leukemia

Abstract

Opinion statementAcute lymphoblastic leukemia (ALL) is the most frequent type of pediatric cancer with a peak incidence at 2–5 years of age. ALL frequently begins in utero with the emergence of clinically silent, preleukemic cells. Underlying leukemia-predisposing germline and acquired somatic mutations define distinct ALL subtypes that vary dramatically in treatment outcomes. In addition to genetic predisposition, a second hit, which usually occurs postnatally, is required for development of overt leukemia in most ALL subtypes. An untrained, dysregulated immune response, possibly due to an abnormal response to infection, may be an important co-factor triggering the onset of leukemia. Furthermore, the involvement of natural killer (NK) cells and T helper (Th) cells in controlling the preleukemic cells has been discussed. Identifying the cell of origin of the preleukemia-initiating event might give additional insights into potential options for prevention. Modulation of the immune system to achieve prolonged immunosurveillance of the preleukemic clone that eventually dies out in later years might present a future directive. Herein, we review the concepts of prenatal origin as well as potential preventive approaches to pediatric B cell precursor (BCP) ALL.

In Utero Origins of Acute Leukemia in Children

“…For instance, CLIC has shown breastfeeding to be protective for both ALL and AML [92], thus it may be particularly fruitful to promote breastfeeding among children at the highest risk of developing leukemia. Others have suggested applying preventative efforts more widely, such as microbiome modification to help prime the developing immune system and prevent overactive immune responses to childhood infections [26,[93][94][95]. Lastly, research to identify currently unknown vulnerabilities in pre-leukemic cells could result in novel preventative strategies not yet imagined.…”

Insights Regarding the Role of Inflammasomes in Leukemia: What Do We Know?

“…Recent investigations have identified some SNVs that cumulatively may provide a high risk for the development of ALL [93]. Due to their multifactorial etiology, it is important to investigate the association of polymorphisms in leukemias, especially in genes of inflammatory pathways, since they may serve as potential predictors for the development and prognosis of leukemias.…”

CircRNA: a rising star in leukemia

“…ALL patients are characterized by an abnormal proliferation and aggregation of lymphocytes in the bone marrow. Lymphocytes are transferred to other tissues and organs, infiltrating systemic organs and tissues, and seriously affecting the hematopoietic function of the bone marrow ( Ruchel et al, 2022 ; Tan, Bertulfo & Sanda, 2017 ). CML is a myeloproliferative neoplasm characterized by the proliferation of clonal hematopoietic stem cells ( Minciacchi, Kumar & Krause, 2021 ; Sampaio et al, 2021 ).…”