NUP98-PHF23 and NUP98-HOXD13 oncogenes confer aberrant self-renewal potential to thymocyte progenitors

Abstract

BackgroundIn T-cell acute lymphoblastic leukemia (T-ALL), the homeobox (HOX) A cluster is activated directly by chromosomal translocations or indirectly by two fusion genes acting as upstream regulators, specifically NUP98-plant homeodomain finger 23 (PHF23) and NUP98-HOXD13. Interestingly, HOXA genes control the self-renewal activity of normal hematopoietic stem cells, suggesting a similar function in cancer stem cells (CSCs). This hypothesis is reinforced by the recent observations that two other oncogenic transcription factors in T-ALL, SCL and LMO1/2, confers self-renewal potential to non-self-renewing thymocyte progenitors.Methods and ResultsHere we used two transgenic mouse models ectopically expressing NUP98-PHF23 and NUP98-HOXD13 in hematopoietic stem/progenitor cells. Our results indicate that pre-leukemic thymocytes exhibit aberrant self-renewal potential as assessed by their engraftment in the thymus after intravenous transplantation. Furthermore, this activity is sustained over serial transplantations with 100-fold expansion of the most primitive thymocyte populations, i.e. DN1 and DN2. At the molecular level, engrafted thymocytes display a non-rearranged bTCR. Finally, purified early T-cell progenitors (ETP) and DN2 are the only cell types that can reconstitute the thymus of transplanted mice, i.e. in cells in which bTcr genes are in a germ line configuration.Conclusion and RelevanceWe therefore conclude that NUP98-PHF23 and NUP98-HOXD13 oncogenes reprogram ETP and DN2 thymocytes into self-renewing progenitors. Our results open possibilities of targeted therapy towards CSCs. BackgroundIn T-cell acute lymphoblastic leukemia (T-ALL), the homeobox (HOX) A cluster is activated directly by chromosomal translocations or indirectly by two fusion genes acting as upstream regulators, specifically NUP98-plant homeodomain finger 23 (PHF23) and NUP98-HOXD13. Interestingly, HOXA genes control the self-renewal activity of normal hematopoietic stem cells, suggesting a similar function in cancer stem cells (CSCs). This hypothesis is reinforced by the recent observations that two other oncogenic transcription factors in T-ALL, SCL and LMO1/2, confers self-renewal potential to non-self-renewing thymocyte progenitors. In T-cell acute lymphoblastic leukemia (T-ALL), the homeobox (HOX) A cluster is activated directly by chromosomal translocations or indirectly by two fusion genes acting as upstream regulators, specifically NUP98-plant homeodomain finger 23 (PHF23) and NUP98-HOXD13. Interestingly, HOXA genes control the self-renewal activity of normal hematopoietic stem cells, suggesting a similar function in cancer stem cells (CSCs). This hypothesis is reinforced by the recent observations that two other oncogenic transcription factors in T-ALL, SCL and LMO1/2, confers self-renewal potential to non-self-renewing thymocyte progenitors. Methods and ResultsHere we used two transgenic mouse models ectopically expressing NUP98-PHF23 and NUP98-HOXD13 in hematopoietic stem/progenitor cells. Our results indicate that pre-leukemic thymocytes exhibit aberrant self-renewal potential as assessed by their engraftment in the thymus after intravenous transplantation. Furthermore, this activity is sustained over serial transplantations with 100-fold expansion of the most primitive thymocyte populations, i.e. DN1 and DN2. At the molecular level, engrafted thymocytes display a non-rearranged bTCR. Finally, purified early T-cell progenitors (ETP) and DN2 are the only cell types that can reconstitute the thymus of transplanted mice, i.e. in cells in which bTcr genes are in a germ line configuration. Here we used two transgenic mouse models ectopically expressing NUP98-PHF23 and NUP98-HOXD13 in hematopoietic stem/progenitor cells. Our results indicate that pre-leukemic thymocytes exhibit aberrant self-renewal potential as assessed by their engraftment in the thymus after intravenous transplantation. Furthermore, this activity is sustained over serial transplantations with 100-fold expansion of the most primitive thymocyte populations, i.e. DN1 and DN2. At the molecular level, engrafted thymocytes display a non-rearranged bTCR. Finally, purified early T-cell progenitors (ETP) and DN2 are the only cell types that can reconstitute the thymus of transplanted mice, i.e. in cells in which bTcr genes are in a germ line configuration. Conclusion and RelevanceWe therefore conclude that NUP98-PHF23 and NUP98-HOXD13 oncogenes reprogram ETP and DN2 thymocytes into self-renewing progenitors. Our results open possibilities of targeted therapy towards CSCs. We therefore conclude that NUP98-PHF23 and NUP98-HOXD13 oncogenes reprogram ETP and DN2 thymocytes into self-renewing progenitors. Our results open possibilities of targeted therapy towards CSCs.