Modelling the role of thymic stromal lymphopoeitin (tslp) and its receptor(tslpr) in acute lymphoblastic leukemia

Thymic stromal lymphopoietin receptor (TSLPR) is commonly deregulated in Philadelphia (Ph)-like subtype of Acute lymphoblastic leukemia.TSLPR consists of cytokine receptor -like factor 2 (CRLF2) and Interleukine-7 receptor Alpha (IL7RA) chains that form heterodimeric signalling complex upon binding TSLP. Cytokine receptor-like factor 2 (CRLF2) is genetically altered in over 50% of the Ph-like ALL cases. Mutant IL7RA, characterised by gain of free cysteine(s) reportedly drives leukemia development in mice and human models independent of CRLF2. Whereas, TSLP is a well-known alarmin that activates immune cells involved in asthmatic response, its role in human B-cell development and leukemia is not well defined. We hypothesized that CRLF2 gene-rearrangements that result in its overexpression may increase TSLPR cell surface density to ‘capture’ limiting TSLP in the microenvironment and promote growth of pre-leukemic/leukemic cells.

To model the influence of TSLP, we expressed both wild-type TSLPR (CRLF2/IL7RA) and mutant TSLPR (CRLF2/IL7RA^{PPCL insert}) in Il3-dependent pro-B BaF3 cells. To explore how TSLP modulates the phenotype of TSLPR-dependent cells, we analysed the transcriptome of mutant TSLPR-BaF3 cells cultured with/without TSLP. Pathway analysis indicated that oxidative phosphorylation (OXPHOS) and Myc target genes were downregulated in mutant TSLPR-BaF3 when cultured with TSLP. We found that both OXPHOS and MYC target genes are downregulated in patients carrying both CRLF2 fusion and IL7RA^S185C mutation compared to patients with CRLF2 fusion and wildtype IL7RA. Overall, our initial findings from both patients and BaF3 models point to the modulation of TP53-MYC gene network by TSLP signalling as probable orchestrators of observed TSLP-dependent metabolic phenotype.