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

Geron, I.; Savino, A. M.; Tal, N.; Fishman, H.; Brown, J.; Turati, V.; James, C.; Sarno, J.; Lee, Y. N.; Rein Gil, A.; Birger, Y.; Muler, I.; Hameiri-Grossman, M.; Marcu-Malina, V.; Parnas, O.; Fischer, U.; Muschen, M.; Borkhard, A.; Kirsch, I. R.; Nagler, A.; Enver, T.; Izraeli, S.

doi:10.1101/2020.01.27.919951

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bioRxiv · 10.1101/2020.01.27.919951

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

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Abstract

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 IL2R{gamma}null 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.

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Geron, I., Savino, A. M., Tal, N., Fishman, H., Brown, J., Turati, V., James, C., Sarno, J., Lee, Y. N., Rein Gil, A., Birger, Y., Muler, I., Hameiri-Grossman, M., Marcu-Malina, V., Parnas, O., Fischer, U., Muschen, M., Borkhard, A., Kirsch, I. R., Nagler, A., Enver, T., Izraeli, S.. 2020-01-28. An instructive role for IL7RA in the development of human B-cell precursor leukemia.. https://doi.org/10.1101/2020.01.27.919951

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