HOXA/PBX3 knockdown impairs growth and sensitizes cytogenetically normal acute myeloid leukemia cells to chemotherapy

Item Type:	Article
Title:	HOXA/PBX3 knockdown impairs growth and sensitizes cytogenetically normal acute myeloid leukemia cells to chemotherapy
Creators Name:	Dickson, G.J. and Liberante, F.G. and Kettyle, L.M. and O'Hagan, K.A. and Finnegan, D.P.J. and Bullinger, L. and Geerts, D. and McMullin, M.F. and Lappin, T.R.J. and Mills, K.I. and Thompson, A.
Abstract:	The cytogenetically normal subtype of acute myeloid leukemia is associated with an intermediate risk which complicates therapeutic options. Lower overall HOX/TALE expression appears to correlate with more favorable prognosis/better response to treatment in some leukemias and solid cancer. The functional significance of the associated gene expression and response to chemotherapy is not known. Three independent microarray datasets obtained from large cohorts of patients along with quantitative polymerase chain reaction validation were used to identify a four-gene HOXA/TALE signature capable of prognostic stratification. Biochemical analysis was used to identify interactions between the four encoded proteins and targeted knockdown used to examine the functional importance of sustained expression of the signature in leukemia maintenance and response to chemotherapy. An 11 HOXA/TALE code identified in an intermediate-risk group of patients (n=315) compared to a group with a favorable risk (n=105) was reduced to a four-gene signature of HOXA6, HOXA9, PBX3 and MEIS1 by iterative analysis of independent platforms. This signature maintained the favorable/intermediate risk partition and where applicable, correlated with overall survival in cytogenetically normal acute myeloid leukemia. We further showed that cell growth and function are dependent on maintained levels of these core genes and that direct targeting of HOXA/PBX3 sensitizes cytogenetically normal acute myeloid leukemia cells to standard chemotherapy. Together the data support a key role for HOXA/TALE in cytogenetically normal acute myeloid leukemia and demonstrate that targeting of clinically significant HOXA/PBX3 elements may provide therapeutic benefit to patients with this subtype of leukemia.
Keywords:	Antineoplastic Agents, Cell Proliferation, Cell Survival, Cytogenetic Analysis, Gene Knockdown Techniques, Homeodomain Proteins, Acute Myeloid Leukemia, Myeloid Ecotropic Viral Integration Site 1 Protein, Neoplasm Proteins, Proto-Oncogene Proteins, U937 Cells
Source:	Haematologica
ISSN:	0390-6078
Publisher:	Ferrata Storti Foundation
Volume:	98
Number:	8
Page Range:	1216-25
Date:	August 2013
Additional Information:	©2013 Ferrata Storti Foundation. This is an open-access paper
Official Publication:	https://doi.org/10.3324/haematol.2012.079012
PubMed:	View item in PubMed

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