In Utero Development and Immunosurveillance of B Cell Acute Lymphoblastic Leukemia.

OPINION STATEMENT: 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.

A brain organoid/ALL coculture model reveals the AP-1 pathway as critically associated with CNS involvement of BCP-ALL.

ABSTRACT: Central nervous system (CNS) involvement remains a clinical hurdle in treating childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The disease mechanisms of CNS leukemia are primarily investigated using 2-dimensional cell culture and mouse models. Given the variations in cellular identity and architecture between the human and murine CNS, it becomes imperative to seek complementary models to study CNS leukemia. Here, we present a first-of-its-kind 3-dimensional coculture model combining human brain organoids and BCP-ALL cells. We noticed significantly higher engraftment of BCP-ALL cell lines and patient-derived xenograft (PDX) cells in cerebral organoids than non-ALL cells. To validate translatability between organoid coculture and in vivo murine models, we confirmed that targeting CNS leukemia-relevant pathways such as CD79a/Igα or C-X-C motif chemokine receptor 4-stromal cell-derived factor 1 reduced the invasion of BCP-ALL cells into organoids. RNA sequencing and functional validations of organoid-invading leukemia cells compared with the noninvaded fraction revealed significant upregulation of activator protein 1 (AP-1) transcription factor-complex members in organoid-invading cells. Moreover, we detected a significant enrichment of AP-1 pathway genes in PDX ALL cells recovered from the CNS compared with spleen blasts of mice that had received transplantation with TCF3::PBX1+ PDX cells, substantiating the role of AP-1 signaling in CNS disease. Accordingly, we found significantly higher levels of the AP-1 gene, jun proto-oncogene, in patients initially diagnosed as CNS-positive BCP-ALL compared with CNS-negative cases as well as CNS-relapse vs non-CNS-relapse cases in a cohort of 100 patients with BCP-ALL. Our results suggest CNS organoids as a novel model to investigate CNS involvement and identify the AP-1 pathway as a critical driver of CNS disease in BCP-ALL.