Oncotarget

Research Papers:

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

Andrew Henry Lewis, Cory Seth Bridges, Viraaj Singh Punia, Abraham Fausto Jornada Cooper, Monica Puppi and H. Daniel Lacorazza _

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Abstract

Andrew Henry Lewis1, Cory Seth Bridges1, Viraaj Singh Punia1, Abraham Fausto Jornada Cooper1,2, Monica Puppi1 and H. Daniel Lacorazza1

1 Department of Pathology & Immunology, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX 77030, USA

2 SMART Program at Baylor College of Medicine Houston, Houston, TX 77030, USA

Correspondence to:

H. Daniel Lacorazza,email: hdl@bcm.edu

Keywords: acute myeloid leukemia; KLF4; cancer; gene editing; cell growth

Received: November 20, 2020     Accepted: January 19, 2021     Published: February 16, 2021

Copyright: © 2021 Lewis et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.


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