In Utero Development and Immunosurveillance of B Cell Acute Lymphoblastic Leukemia

Abstract

Acute 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.

Keywords: Acute lymphoblastic leukemia; Cancer predisposition; ETV6-RUNX1; High hyperdiploidy; Preleukemic clone; Trained immunity.

Figure 1

Immunosurveillance of the preleukemic clone. Germline and acquired somatic mutations predispose towards leukemia and define distinct ALL subtypes. Via a dysregulated immune response, infections can trigger transformation of the preleukemic clone into overt leukemia. This process is under constant immunosurveillance. T helper (Th) 1 cells can favor leukemia development via upregulation of CD38 and interferon gamma-induced protein 10 (IP-10), mediated by activation-induced cytidine deaminase (AID). Th2 cells on the other hand can inhibit leukemia development. Natural killer (NK) cells play an important role in cancer surveillance. They can favor development of overt leukemia by up- or downregulation of different factors, such as HLA-C2, KIR2DL1, KIR2DL5A, PI-9, NKp46, FasL, and granzyme B. Apoptosis of the preleukemic clone can be mediated by NKG2C⁽⁺⁾ NK cells. SNP, single nucleotide polymorphism; IL7R, interleukin-7 receptor alpha.