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

Abstract

Pediatric chronic myeloid leukemia (CML) is a rare hematological malignancy with biological features that differ from that of adult patients. In pediatric CML patients 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 non-hematologic 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 chronic phase CML (CP-CML) pediatric patients 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 CML patients by targeting NAMPT-mediated deacetylation of the hematopoietic-specific HCLS1 protein. Teaser Abstract Pediatric chronic myeloid leukemia (CML) patients need long-term tyrosine kinase inhibitor treatment which causes toxicities. Therefore, improvements of CML therapy in pediatric patients are needed. Here, we report elevated levels of the Nicotinamide phosphoribosyltransferase (NAMPT) in chronic phase pediatric CML cells. NAMPT inhibition abrogated in vitro clonogenic capacity and proliferation of CML cells. NAMPT deacetylates and activates the hematopoietic-specific lyn-substrate 1 (HCLS1) protein. Moreover, IL1RAP - a marker of myeloid leukemia initiating cells - is a downstream target of NAMPT/HCLS1 pathway. Together, our results reveal new treatment avenues of pediatric CML patients.