An instructive role for IL7RA in the development of human B-cell precursor leukemia.
Ifat Geron, et al.
Received Date: 13th May 20
Ifat Geron, Angela Maria Savino, Noa Tal, John Brown, Virginia Turati, Chela James, Jolanda Sarno, Yu Nee Lee, Avigail Rein Gil, Hila Fishman, Yehudit Birger, Inna Muler, Michal Hameiri-Grossman, Kara Lynn Davis, Victoria Marcu-Malina, Oren Parnas, Ute Fischer, Markus Müschen, Arndt Borkhardt, Ilan Richard Kirsch, Arnon Nagler, Tariq Enver, Shai Izraeli
B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is preceded by a clinically silent pre-leukemia. Experimental models that authentically re-capitulate disease initiation and progression in human cells are lacking. We previously described activating mutations in interleukin 7 receptor alpha (IL7RA) that are associated with the poor-prognosis Philadelphia-like (Ph-like) subtype of BCP-ALL. Whether IL7RA signaling has a role in initiation of human BCP-ALL is unknown.
IL7RA is essential for mouse B-cell development; however, patients with truncating IL7RA germline mutations develop normal mature B-cell populations. Herein, we explore the consequences of aberrant IL7RA signaling activation in human hematopoietic progenitors on malignant B-cell development.
Transplantation of human cord-blood hematopoietic progenitors transduced with activated mutant IL7RA into NOD/LtSz-scid IL2Rγnull mice resulted in B-cell differentiation arrest with aberrant expression of CD34+ and persistence of pro-B cells that survive despite failing to achieve productive rearrangement of immunoglobulin V(D)J gene segments. Activation of IL7RA signaling enhanced self-renewal and facilitated the development of a BCP-ALL in secondary transplanted mice. The development of leukemia was associated with spontaneous acquired deletions in CDKN2A/B and IKZF1 similar to what is observed in Ph-like BCP-ALL in humans. Single cell gene expression analysis suggested that pre-leukemic cells resided within a subpopulation of early B-cell precursors with CD34+CD10highCD19low immunophenotype.
The development of a bona fide BCP-ALL from IL7RA transduced cells supports the hypothesis that aberrant activation of the IL7RA pathway in human B-cell lineage progenitors has an instructive role by creating a pre-leukemic state which is vulnerable to transformation. These are the first demonstrations of a role for IL7RA in human B-cell differentiation and of a de-novo Ph-like BCP-ALL development from normal human hematopoietic progenitors in vivo.
Read in full at bioRxiv.
This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.