Abstract
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 stem and progenitor cells induces a preleukemic state in transplanted immunodeficient 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 evolve into BCP-ALL with spontaneously acquired Cyclin Dependent Kinase Inhibitor 2 A (CDKN2A) deletions, as commonly observed in primary human BCP-ALL. CRISPR mediated gene silencing of CDKN2A in primary human CD34+ cells transduced with activated IL7RA results in robust development of BCP-ALLs in-vivo. Thus, we demonstrate that constitutive activation of IL7RA can initiate preleukemia in primary human hematopoietic progenitors and cooperates with CDKN2A silencing in progression into BCP-ALL.
Highlights
Kinase signaling fuels growth of B-cell precursor acute lymphoblastic leukemia (BCP-ALL)
The activity of the Interleukin-7 receptor alpha (IL7RA)/ cytokine receptor-like factor 2 (CRLF2) transgenes was verified by STAT5 phosphorylation assay in a BCP-ALL cell line (Supplementary Fig. 2)
This observation places emphasis on understanding how the preleukemic phase is initiated and how the responsible lesions can pre-dispose cells for subsequent frank transformation. We explored this issue in the most common subtype of the poor-prognosis Philadelphia-like (Ph-like) B-cell precursor acute lymphoblastic leukemia (BCP-ALL). This variant is commonly associated with aberrant expression of cytokine receptor-like factor 2 (CRLF2) which dimerizes with Interleukin-7 receptor alpha (IL7RA) to form the receptor for Thymic Stromal Lymphopoietin (TSLP)[9]
Summary
Kinase signaling fuels growth of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). We demonstrate that constitutive activation of IL7RA can initiate preleukemia in primary human hematopoietic progenitors and cooperates with CDKN2A silencing in progression into BCP-ALL. “Ph-like” leukemia is a subgroup of high-risk BCP-ALLs caused by activation of signaling leading to a similar gene expression signature to BCR-ABL1 (“Philadelphia”) ALL14–16. The majority of these leukemias are characterized by aberrant expression of CRLF2/IL7RA and mutations activating JAK-STAT signaling[17]. We provide an experimental evidence in human hematopoietic cells that expression of activated IL7RA (IL7RAins) has an instructive role in human B-cell development by initiating a preleukemic state that is vulnerable to evolve to overt “Ph-like” BCP-ALL. We further demonstrate that the loss of cyclindependent kinase inhibitor 2A (CDKN2A) cooperates with IL7RA in the development of BCP-ALL
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