Abstract
Genetic heterogeneity is the basis of clinical heterogeneity among different subtypes of AML. We have successfully cloned a gene related to AML termed FAMLF from a FAB-M2 patient's sample of a second largest AML pedigree. Then we revealed at least three splice variants, named as FAMLF-1, FAMLF-2 and FAMLF-3, and found miR181a1/b1 in the second intron of FAMLF gene family. Higher expression of FAMLF-1 was related to a higher complete remission (CR) rate, but shorter relapse free survival (RFS) in AML. We further found that the FAMLF-1 single nucleotide polymorphism (SNP) haplotype and its expression were positively correlated to clinical parameters of acute myeloid leukemia partially differentiated (FAB-M2) patients, but not FAB non-M2 patients or Acute Monocytic Leukemia (FAB-M5) patients. GTAGG SNP haplotype of FAMLF gene might increase FAB-M2 susceptibility in Han population and act as a useful candidate biomarker for FAB-M2 screening. We also demonstrated that FAMLF-1 gene silencing in FAB-M2 cells could lead to proliferation inhibition, cell cycle G0/G1 phase arrest, and differentiation promotion independent of its intronic miR-181a1, which might be related to Akt/c-Myc pathway. These findings reveal a role of FAMLF-1 as a potential pathogenic gene for FAB-M2.
Highlights
Acute myeloid leukemia (AML) is a clinically and genetically highly heterogeneous disease that accounts for 65.7% of acute leukemia [1]
We further found that the familial www.impactjournals.com/oncotarget acute myelogenous leukemia related factor (FAMLF)-1 single nucleotide polymorphism (SNP) haplotype and its expression were positively correlated to clinical parameters of acute myeloid leukemia partially differentiated (FAB-M2) patients, but not French– American–British classification systems (FAB) Non Acute Myeloid Leukemia Partially Differentiated (non-M2) patients or Acute Monocytic Leukemia (FAB-M5) patients
FAMLF splice variant 1 (FAMLF-1) expression in Acute Myeloid Leukemia Partially Differentiated (FAB-M2) was correlated with WBC count (P = 0.0019), hemoglobin level (P = 0.0011), percentage of peripheral blood blasts (P < 0.0001), Hydroxybutyrate dehydrogenase (HBDH) level (P= 0.0025; Online Supplementary Table 2)
Summary
Acute myeloid leukemia (AML) is a clinically and genetically highly heterogeneous disease that accounts for 65.7% of acute leukemia [1]. The prognosis of AML has improved, approximately 60–70% of AML patients experience long-term survival [2]. FAB-M2 and FAB-M5 are both the most common morphologically classified subtypes of AML, the former has better OS than the latter among every age groups [1]. Long-term OS of non-M3(including FAB-M2 and FAB-M5) subtypes is still poor. Genetic heterogeneity including gene mutation and expression abnormity is the basis of these clinical heterogeneity among different subtypes of AML [4, 5]. Discovering and studying novel AML related genes may help to illustrate the leukemogenesis mechanism, especially to improve treatment outcomes of FAB non-M3
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