An instructive role for IL7RA in the development of human B-cell precursor leukemia

Kinase signaling fuels growth of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Yet
its role in leukemia initiation is unclear and has not been shown in primary human hematopoietic
cells. We previously described activating mutations in interleukin-7 receptor alpha (IL7RA) in
poor-prognosis “ph-like†BCP-ALL. Here we show that expression of activated mutant IL7RA in
human CD34+ hematopoietic cells creates a preleukemic state in transplanted NOD/LtSz-scid
IL2Rγnull mice, characterized by persistence of self-renewing Pro-B cells with non-productive
V(D)J gene rearrangements. Preleukemic CD34+CD10highCD19+ cells evolved to a BCP-ALL with
spontaneously acquired CDKN2A deletions as commonly observed in primary human BCP-ALL.
CRISPR mediated silencing of CDKN2A in primary human CD34+ cells transduced with activated
IL7RA resulted in robust development of BCP-ALLs in-vivo. Thus, we demonstrate for the first
time that constitutive activation of IL7RA can initiate preleukemia in primary human hematopoietic
progenitors and cooperates with CDKN2A silencing in progression into BCP-ALL.EGA study EGAS00001005347