Activation of IL7RA signalling in human B-lymphoid precursors induces pre-leukemia

ABSTRACT: Childhood acute lymphoblastic leukemia (ALL) is preceded by a clinically silent pre-leukemia. Experimental models that authentically re-capitulate disease initiation and progression in human cells are lacking. Herein, we explore these issues in the most common subtype of the poor-prognosis Philadelphia-like (Ph-like) B-cell precursor (BCP) ALL, characterized by aberrant expression of cytokine receptor-like factor-2 (CRLF2) which dimerizes with Interleukin-7 receptor alpha (IL7RA). Whether CRLF2/IL7RA signalling has a role in initiation of human BCP-ALL is unknown. To investigate this, we expressed CRLF2 and/or mutationally activated IL7RA in cord-blood CD34+ hematopoietic progenitors and transplanted them into NOD/LtSz-scid IL2Rγnull mice. Detailed immunphenotypic and molecular analyses revealed that activation of the CRLF2/IL7RA pathway induces B-cell differentiation arrest coupled with enhanced self-renewal in-vivo, consistent with a pre-leukemic state. Progression from pre-leukemia to leukemia in children is rare and associated with an intervening period of several years. Nevertheless, we observed the development of BCP-ALL after a secondary transplant of pre-leukemic cells transduced with mutationally-activated IL7RA. Genomic analysis of the leukemia revealed the loss of CDKN2A/B and IKZF1, typically observed in Ph-like ALL. Single cell gene expression analysis of pre-leukemic and leukemic cells further suggests that the leukemia arose from a subpopulation of CD19+CD10highCD34+ pre-leukemic cells. The development of authentic BCP-ALL from CRLF2/IL7RA transduced cells supports the hypothesis that aberrant activation of the CRLF2/IL7RA pathway in human B-cell lineage progenitors creates pre-leukemic state which is vulnerable to transformation. This is the first model of a de-novo Ph-like BCP-ALL development from normal human hematopoietic progenitors in vivo.

PROVIDER: EGAS00001003979 | EGA |

REPOSITORIES: EGA