Signals from the bone marrow B cell niches shape pre-leukemic fate in a murine model of B cell acute lymphoblastic leukemia.

The bone marrow (BM) microenvironment plays a key role in supporting B cell development. In acute lymphoblastic leukemia (B-ALL), the acquisition of oncogenic driver mutations blocks B cell differentiation at specific stages. When these pre-leukemic cells acquire secondary mutations, B-ALL develops. However, the role of the BM microenvironment in pre-leukemic cell fate remains unknown. Here, using a murine model of spontaneous B-ALL development, we show that disrupted pre-BCR signaling in pre-leukemic cells modifies their fate. Blocking expression of the pre-BCR ligand Galectin-1 by the microenvironment impaired pre-leukemic cell proliferation and leukemia-initiating capacity. Consequently, B-ALL development was delayed, and B-ALL had a more mature phenotype, with cells expressing a BCR. Secondary mutations were also altered by changes to Galectin-1 expression. In its absence, mutations almost exclusively affected IL-7R signaling rather than both pre-BCR and IL-7R signaling. These results demonstrate that signals from bone marrow (BM) niches trigger leukemogenesis in cooperation with driver mutations and determine the fate of pre-leukemic B cells.