Loss of Krüppel-Like Factor 4 (KLF4) Impairs the Self-Renewal of Leukemic Stem Cells

Abstract 911 The identification of pathways that differentially regulate the self-renewal in normal hematopoietic stem cells (HSC) and leukemic stem cells (LSC) is critical for effective treatment of relapsed leukemia without affecting normal hematopoiesis. Kruppel-like factor 4 ( KLF4) is a bi-functional transcription factor that can either activate or repress transcription and thus function as an oncogene or a tumor suppressor depending on the cellular context. We have previously shown that loss of KLF4 leads to increased self-renewal of HSC in serial bone marrow transplantation. In this work, we investigated whether KLF4 also regulates self-renewal in LSCs using a mouse model of somatic deletion of KLF4 in hematopoietic cells ( Klf4 fl/fl Vav-iCre + ) and the BCR-ABL-induced chronic myeloid leukemia (CML) model. Mice transplanted with wild type bone marrow (BM) cells transduced with retrovirus carrying BCR-ABL (p210) (n=18) showed an expansion of myeloid cells (GFP + Gr1 + ) with a median survival of 19 days. In contrast, mice transplanted with KLF4-deficient BM cells transduced with BCR-ABL retrovirus (n=12) exhibited prolonged survival with a median survival of 27 days (p + Gr1 + ) in the first two weeks after BM transplant, which was followed by a progressive loss of myeloid cells and an expansion of B cells (GFP + B220 + ). In control group, 90% of leukemic mice succumbed from CML whereas more than 50% of KLF4-deficient leukemic mice developed mixed CML and B-ALL leukemia. These results suggest that loss of KLF4 impairs the maintenance of BCR-ABL-induced CML, while allowing expansion of BCR-ABL positive B cells (GFP + B220 + ). Since KLF4 deletion prevented continuous expansion of myeloid leukemic cells (GFP + Gr1 + ), we postulated that KLF4 may be critical to LSC maintenance. Thus, we analyzed the frequency of LSCs (GFP + Lin – c-Kit + Sca-1 + and GFP + Lin – c-Kit + Sca-1 + Flt3 – ) in BM and the spleen. We found that LSCs were significantly reduced in recipients of BCR-ABL-transduced KLF4-deficient BM cells 18 days after transplantation (n=6, p Disclosures: No relevant conflicts of interest to declare.