NAMPT-mediated deacetylation of HCLS1 protein promotes clonogenic growth of pediatric CML cells.

Abstract

Pediatric chronic myeloid leukemia (CML) is a rare hematologic malignancy with biological features that differ from that of adult patients. In pediatric patients with CML the burden of tumor cells is higher resulting in a delayed achievement of deep molecular response (DMR) upon treatment with tyrosine kinase inhibitors (TKIs, e.g., imatinib) than what has been reported in adults. Therefore, the probability to develop resistance to TKIs in children with CML is higher than in adults due to much longer exposure to TKIs. Moreover, in children with CML, long-term treatment with imatinib causes hematologic and nonhematologic toxicities. Improvements of CML therapy in pediatric patients based on the targeting of hematopoiesis-specific BCR::ABL1 downstream effectors are needed. Here, we report elevated levels of the nicotinamide phosphoribosyltransferase (NAMPT) in mononuclear cells of pediatric patients with chronic phase CML (CP-CML) and in blastic phase CML cell lines. NAMPT inhibition abrogated in vitro clonogenic capacity and proliferation of CML cells. NAMPT deacetylates and activates the hematopoietic-specific lyn-substrate 1 (HCLS1) protein, which is essential for the proliferation of CML cells. Moreover, IL1RAP - a marker of myeloid leukemia-initiating cells - and LEF-1 - a transcription factor of Wnt signaling - are downstream targets of NAMPT/HCLS1 pathway. Together, our results reveal new treatment avenues of pediatric patients with CML by targeting NAMPT-mediated deacetylation of the hematopoietic-specific HCLS1 protein.