| This thesis consists of two parts: 1.Impact of blood count recovery on outcomes of acute myeloid leukemia patients achieving morphologic leukemia-free state;2.Downstream regulation of epigenetic related genes MLL and DNMT3 A mutations in acute myeloid leukemia.Part 1Impact of Blood Count Recovery on Outcomes of Acute Myeloid LeukemiaPatients Achieving Morphologic Leukemia-free StateAchievement of complete remission(CR)is associated with good long-term outcomes in patients with acute myeloid leukemia(AML),however,a proportion of patients can only achieve CR with incomplete hematologic recovery(CRi),a response less than CR,whose clinical relevance and prognostic significance remain to be explored.A total of 350 consecutive newly diagnosed non-M3 adult AML patients were enrolled in this study,among which,230 patients achieved either CR(n=179)or CRi(n=51)after the initial two courses of chemotherapy,we evaluated the differences between the two groups concerning clinical and laboratorial characteristics and survival.Patients with CRi had lower platelet count at diagnosis.Biallelic CEBPA mutations were more frequently while C-KIT mutations were less frequently seen in CRi group.Minimal residual disease(MRD)level after induction therapy was higher in patients with CRi than those who achieved CR.Survival analysis indicated that achievement of CRi rather than CR was an independent factor predicting shorter relapse-free survival(RFS)and overall survival(OS),which couldn’t be observed in patients who received hematopoietic cell transplantation(HCT).Age,MLL fusion genes,MLL-PTD as well as C-KIT mutations were also factors exerting prognostic effect on relapse or survival in multivariate analysis.Our study demonstrates that CRi conveys prognostic information as a separate response in patients with AML,and should be considered in therapeutic decision-making after achieving morphologic leukemia-free state(MLFS).Part 2 Downstream Regulation of Epigenetic Related Genes MLL and DNMT3 A Mutations in Acute Myeloid LeukemiaWith the development of next generation sequencing(NGS),more and more gene mutations and transcriptional abnormalities have been found to be associated with the pathogenesis and prognosis of leukemia,which provides the foundation for further prognostic stratification of acute myeloid leukemia(AML).Epigenetic gene abnormalities play an important role in the malignant transformation of leukemia cells and are important risk factors for AML.Epigenetic related genes DNMT3 A mutations and MLL fusion genes are frequently seen in M4/M5 subtype with mutually exclusive,both of which are associated with increased age,higher white blood count at diagnosis and poor prognosis.In this study,we collected 13 and 14 AML patients carrying MLL fusion genes and DNMT3 A mutations,respectively,and performd RNA-seq using bone marrow specimens.Gene expression profiles in the two groups of patients showed their own clustering characteristics.In analysis of differentially expressed genes,we found that multiple genes belonging to HOXB family are highly expressed in patients with DNMT3 A mutations.Two genes of the same family,PRDM16 and MECOM,are highly expressed in patients carrying the DNMT3 A mutations and the MLL fusion genes,respectively,which may exert a similar effect in the downstream pathways of these two epigenetic abnormalities.In conclusion,DNMT3 A mutations and MLL fusion genes demonstrate mutually exclusive enrichment in M4/M5 subtype AML as well as similar clinical and biological behaviors,and their transcriptionally regulated downstream genes PRDM16 and MECOM are highly homologous,which indicates that DNMT3 A mutations and the MLL fusion genes share a common signalling pathway.Functional experiments based on PRDM16 and MECOM genes may be a promising research direction for studying the pathogenesis of AML induced by DNMT3 A mutations and MLL fusion genes. |
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