Abstract
Adult acute myeloid leukemia (AML) patients with biallelic mutations of CEBPA (biCEBPA) displays a favorable clinical outcome, and is defined as a unique entity in the 2016 World Health Organization classification. However, due to the intrinsic characteristics of the mutation, existence of co-occurring mutations and diversified gene expression signature, the prognosis of these patients needs to be analyzed in a more systematic way. In this study we evaluated the genetic characteristics and clinical outcome in a cohort of 137 biCEBPA AML cases, and proposed a prognostic nomogram to predict the overall survival (OS) of based on the clinical variables selected by multivariate Cox regression model in training cohort, including age, white blood cell count, co-existence of DNMT3A and CSF3R mutation and whether patients could achieve complete remission after induction therapy. The area under the receiver operating characteristic (ROC) curves for 3 and 5-year OS were 0.833 and 0.863, respectively. RNA sequencing of 4 relapsed patients showed that over-expression of VMP1 was an indicator of poor prognosis of biCEBPA AML patients. In conclusion, this prognostic nomogram might provide a more accurate prediction of the clinical outcomes of biCEBPA AML patients.
Highlights
CCAAT/enhancer binding protein a (CEBPA) plays a pivotal role as a transcription factor in both self-renewal of hematopoietic stem cells (HSCs) and proliferation and differentiation of myeloid progenitor cells
acute myeloid leukemia (AML) patients with Biallelic CEBPA (biCEBPA) mutation were associated with longer survival, the heterogeneity of these patients was reported in recent years [9]
We aimed to estimate the probability of 5-year overall survival (OS) based on a multivariate Cox proportional hazards model that included five clinical variables at the onset of diagnosis, including age, white blood cell count, co-existence of DNMT3A mutation and/or CSF3R mutation and complete remission is achieved after induction therapy
Summary
CCAAT/enhancer binding protein a (CEBPA) plays a pivotal role as a transcription factor in both self-renewal of hematopoietic stem cells (HSCs) and proliferation and differentiation of myeloid progenitor cells. Major CEBPA mutated AML cases carry two mutations, one in the N-terminal of the protein and the other one in the basic leucine zipper (bZIP) domain. N-terminal nonsense and frameshift mutations truncate the CEBPA protein and lead to a dominant negative effect, while mutations in the bZIP domain at the C terminus are generally in-frame insertions or deletions which brings disrupted DNA binding and dimerization [1, 2]. Biallelic CEBPA (biCEBPA) mutations are detected in 2-15% of de novo acute myeloid leukemia (AML) patients, and are associated with a favorable clinical outcome compared to wildtype or monoallelic CEBPA mutation [3]. Around 40% patients could relapse after conventional chemotherapy, indicating a blatant heterogeneity within this disease entity [7, 8]
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