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.
Highlights
Acute myeloid leukemia (AML) is a malignant hematological disease that arises from genetic lesions in hematopoietic cells early in the hierarchy of normal myelopoiesis and a difficult to treat leukemia because of complexity of mutations and chromosomal translocations
Further analysis of Krüppel-like factor 4 (KLF4) transcript levels and DNA methylation revealed no significant correlation in AML while the levels of KLF4 correlated with gene methylation in other types of cancer (Figure 1B)
To further evaluate whether DNA methylation is involved in the regulation of KLF4 expression, we treated a panel of AML (NB4, THP-1, MonoMac-6, SKM-1), chronic myeloid leukemia (CML) (K562), and EBV-transformed lymphoblastoid (LCL) cell lines with the hypomethylating agent 5-Azacytidine (5-aza)
Summary
Acute myeloid leukemia (AML) is a malignant hematological disease that arises from genetic lesions in hematopoietic cells early in the hierarchy of normal myelopoiesis and a difficult to treat leukemia because of complexity of mutations and chromosomal translocations. The lack of mutations and genetic alterations suggest that KLF4 may be required for disease progression [27] whereas studies using the Cancer Genome Atlas have shown that KLF4 expression is not uniform among AML patients, but is generally lower than normal blood cells [7, 28] and associated with leukemia stage [22, 28, 29] These findings have fueled a presumption of tumor-suppressive function for KLF4 in AML, a model of ZMYM2-FGFR1 leukemia suggests KLF4 may be involved in AML leukemogenesis [30]. These observations highlight a need to better define the role of KLF4 in leukemia and in particular AML
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