2002 – MATRICELLULAR PROTEIN DEFICIENCY TRANSFORMS MDS TO MYELOID LEUKEMIA THROUGH INDUCTION OF TGF-Β-MEDIATED EPITHELIAL-TO-MESENCHYMAL TRANSITION

Acute myeloid leukemia (AML) often arises from myelodysplasia (MDS), a pre-leukemic condition characterized by dysplasia and ineffective hematopoiesis. Using mouse models of MDS and AML we identified a global decrease in nucleoporin (NUP) expression that was confirmed in publicly available patient databases. shRNA-mediated downregulation of NUPs in mouse MDS HSPCs and transplantation led to fully penetrant AML with blasts in blood, bone marrow (BM) and spleen. To examine the relevance of NUPs in human disease we downregulated NUPs expression in a model of induced Pluripotent Stem Cell (iPSC)-derived HSPCs harboring the MDS-relevant SRSF2P95L and ASXL1646fs*12 mutations (SA). shNUPS-SA HSPCs overcame exhaustion and loss of CD34 expression, typical of MDS cells. Transformed cells maintained growth for as long as 10 months, acquired phenotypic characteristics of AML blasts and presented a 2.5-fold upregulation of the leukemic biomarker CD123. shNUPS-SA HSPCs engrafted in NSG mice, establishing the transformative potential of NUP downregulation in a humanized in vivo model. RNAseq analysis of HSPCs from mouse and human models of AML versus MDS and patient samples revealed upregulation of genes promoting epithelial-to-mesenchymal transition (EMT). Master regulator analysis between patient-derived MDS and AML HSPCs and their stroma identified the secreted matricellular protein Tenascin X as a candidate regulator of NUPs expression. TNXB levels decreased in BM plasma of AML as compared to MDS patients and in the BM of AML as compared to MDS mice. Mass spectrometry analysis identified the presence of a TNXB protein mainly consisting of the fibrinogen-like domain linked to active TGF-β-mediated activation of EMT. The identification of EMT as a signature of transformation in a non-solid cancer uncovers a novel pathway of AML invasiveness that could be potentially targetable.