The PHF6 - TLX1 cooperativity and the IL7R-JAK3 signaling axis as drug target in PHF6 deficient T-ALL

01 January 2015 → 31 December 2015
Research Foundation - Flanders (FWO)
Research disciplines
  • Natural sciences
    • Genetics
    • Systems biology
  • Medical and health sciences
    • Molecular and cell biology
    • Molecular and cell biology
PHF6 deficient T-ALL
Project description

T -cell acute lymphoblastic leukemia (T -ALL) arises from uncontrolled proliferation and arrested differentiation of precursor T-cells. Since many factors contributing to the pathogenesis of T-ALL are still unknown, a comprehensive analysis of the molecular pathways involved in this disease will be crucial to fully understand the mechanisms of malignant T-cell transformation and to develop novel strategies for targeted and less toxic
treatment of T-ALL patients. Our research team identified PHF6 as a novel tumor suppressor gene in T-ALL [1]. Inactivating mutations and deletions were found in PHF6 in 16% of pediatric and 38% of adult T-ALL patients and are predominantly enriched within the TLX113 genetic subgroup of T-ALLs. Despite the high mutation frequency of this tumor suppressor in T-ALL, the specific cellular functions of PHF6 and its role in T-ALL formation remain elusive. In this research project, we used an integrative genomics approach to unravel the
transcriptional network downstream of PHF6 in T-ALL Iymphoblasts and progenitor T-cells. Amongst others, I could identify the interleukin-7 receptor (lL7R), a known T-ALL oncogene, as one of the most robust PHF6 negatively regulated targets both in T -ALL cells and T-cell progenitors. Furthermore, a significant association of PHF6 loss-of-function mutations and JAK3 activating mutations was observed when screening a large cohort of
primary T-ALLs. Given the drugability of the IL7R-JAK-STAT pathway, this discovery creates a unique perspective for a new way of therapeutic intervention for PHF6 mutated T-ALLs. By serendipity, I also discovered that TLX1, an important driver oncogene in T-ALL, also represses IL7R transcription. At first, this was counterintuitive given the essential role of IL7R for survival and growth of the leukemic cells. However, together with the novel insights on PHF6 described above, I can now hypothesize that the convergence of PHF6 and
TLX1 to IL7R expression regulation is a key feature for their cooperativity in T-ALL leukemogenesis. Finally, in collaboration with the Taghon team at Ghent University, I could also gain insights into the physiological effects of perturbed PHF6 expression on normal lymphoid lineage development and observed profound effects on both Tand B-cell differentiation. Given these exciting novel insights mainly emerged during the last year of my IWT grant, I would like to finalize my research on this topic using this VLK grant in order to make a complete story to submit to a high impact journal. The specific goals that I aim to achieve are: 1) complete ongoing experiments regarding the PHF6-IL7R axis in T-ALL pathogenesis and i~s potential therapeutic implications using both in vitro and in vivo model systems, 2) evaluate the functional"\cooperativity between PHF6 and TLX1 in T-ALL oncogenesis with respect to their impact on IL7R-JAK-STAT signaling and 3) to write up these findings in a highimpact publication and finalize my PhD thesis. Given the research experience I gained during this PhD thesis project and the excellent expertise of both the host lab and the collaborators involved in this project, I am confident that the proposed goals will be achieved within the period of one year.