Krüppel-like factor 4 promotes survival and expansion in acute myeloid leukemia cells

Abstract

Acute myeloid leukemia (AML) is an aggressive hematological malignancy of the bone marrow that affects mostly elderly adults. Alternative therapies are needed for AML patients because the overall prognosis with current standard of care, high dose chemotherapy and allogeneic transplantation, remains poor due to the emergence of refractory and relapsed disease. Here, we found expression of the transcription factor KLF4 in AML cell lines is not silenced through KLF4 gene methylation nor via proteasomal degradation. The deletion of KLF4 by CRISPR-CAS9 technology reduced cell growth and increased apoptosis in both NB4 and MonoMac-6 cell lines. Chemical induced differentiation of gene edited NB4 and MonoMac6 cells with ATRA and PMA respectively increased apoptosis and altered expression of differentiating markers CD11b and CD14. Transplantation of NB4 and MonoMac-6 cells lacking KLF4 into NSG mice resulted in improved overall survival compared to the transplantation of parental cell lines. Finally, loss-of-KLF4 did not alter sensitivity of leukemic cells to the chemotherapeutic drugs daunorubicin and cytarabine. These results suggest that KLF4 expression supports AML cell growth and survival, and the identification and disruption of KLF4-regulated pathways could represent an adjuvant therapeutic approach to increase response.

The high-performance technology CRISPR/Cas9 improves knowledge and management of acute myeloid leukemia

“…Transplantation of NB4 and MonoMac-6 cells after genetically engineered modification into NSG mice resulted in prolonged overall survival. KLF4 gene loss did not decrease the sensitivity of leukemic cells to chemotherapy with products such as cytarabine and daunorubicin 1 .…”

“…Acute myeloid leukemia (AML) is an aggressive malignant hemopathy. Its prognosis continues to be poor with the current standard of care, as in many patients, the disease relapses or becomes refractory 1 . It is unanimously accepted that new therapies are needed to improve AML patients survival 2 .…”

KLF4-mediated upregulation of the NKG2D ligand MICA in acute myeloid leukemia: a novel therapeutic target identified by enChIP

“…KLF4 has been shown to function as a tumor suppressor or oncogene in cell-dependent contexts [ 33 ]. Although the role of KLF4 in AML is controversially discussed, it has been shown to play an oncogenic role in AML cell lines and the deletion of KLF4 by CRISPR/Cas9 suppresses cell growth and induces apoptosis [ 34 ]. These experiments were, however, performed in immunodeficient mouse models, and a putative innate immune response to NKG2D-L positive AML was not addressed.…”