| Summary: | 博士 === 國立臺灣大學 === 臨床醫學研究所 === 101 === Acute myeloid leukemia(AML）is the most common leukemia in adults. AML is a hematological malignancy characterized with abnormal proliferation of hematopoietic progenitors. Infection is the most common complication in the AML patients, and intracranial hemorrhage (ICH) is the second common complications. We investigated the epidemiological data of these clinical issues in Taiwan, and this result potentially can benefit the AML patients in the future.
Cancer is a heterogeneous clonal disease. Leukemia development is usually a multistep process and arises from accumulated several genetic mutations. Recently, the prognosis in AML patients could be stratified by cytogenetics and molecular gene mutations. To know the genetic mutations can help the disease diagnosis and follow-up. We used the polymerase chain reaction and Sanger sequencing to find the epidemiology of genetic mutations and clinical characteristics in AML patients. We also used the technique of next generation sequencing to find the novel fusion genes in the complex karyotype AML.
Method
1. Survey the epidemiology and clinical manifestations of opportunistic infection、 intracranial hemorrhage in the adult patients with AML.
2. Detect the genetic mutations in adult patients with AML by the PCR and Sanger sequencing and correlate with clinical characteristics; Use the technique of next generation sequencing to detect the genetic lesions in the complex karyotype AML.
Result and Discussion
The incidence of AML is increasing in Taiwan. The incidence is 2.93 per 100000 populations in male and 2.62 per 100000 populations in female.
Two large scale retrospective studies of blood stream infection in the patients with hematological malignancy were investigated in 1996~2001 and 2002~2006. Gram negative bacteria were about 60% of pathogens, Gram positive bacteria were 30%, and the others were candida and anaerobes. E. coli and Klebsiella were the most common pathogens of Gram negative bacteria. Coagulase negative staphylococcus and streptococcus viridans were the most common Gram positive bacteria.
We also investigated the clinical characteristics of fungus, mycobacterium tuberculosis and non-tuberculosis mycobacterium in Taiwan. Candida tropicalis was the most common pathogen of candidemia. Aspergillus flavus was the most common mold in the invasive fungal sinusitis. The patients with AML tended to developed invasive fungal sinusitis and tuberculosis than patients with other hematological malignancy.
We retrospectively reviewed 841 AML patients between 1995 and 2007. Most AML patients with ICH were in refractory and relapsed status. Multivariate analysis revealed four independent prognostic factors: prolongation of prothrombin time (INR>1.5)、brainstem hemorrhage、subarachnoid hemorrhage and epidural hemorrhage。 The most common sites of ICH in AML patients included cerebral cortex (60 cases, 83％）、basal ganglion (13 cases,18％）、cerebellum(10 cases, 14％）and brainstem（5 cases,7％）. There were 33 cases (46%) with multifocal hemorrhage. The locations and types of ICH in neuroimaging could predict prognosis in AML patients.
Cytogenetics and molecular genetic mutation can predict the prognosis in AML.We found distinct clinical characteristics and prognosis in AML patients with genetic mutation of NPM1, CEBPA, RUNX1, or so on. Hierachical cluster analysis of the immunophenotype could stratify AML patients with NPM1 mutation into two groups with distinct prognosis. Patients whose immunophenotypes showed positive expression of HLADR, CD34, and CD7 had worse prognosis.
We detected new fusion transcripts by the technique of bioinformatics and next generation sequencing. Five fusion transcripts were found, including NSD1-NUP98 and CBFB-MYH11, that had been reported before, and three novel fusion transcripts TPM4-KLF2, TALDO1-DSN1,and KIAA0430-CES3.
DSN1 is the component of kinetochore. Kinetochore involves in the mitotic process of chromatids during cell division into two daughter cells.We predict the complex karyotype of AML patients could be related to the dysfunction of mitosis associated (DSN1) gene.
Conclusion
We studied the clinical manifestations and prognosis of opportunistic infection in AML patients. The neuroimaging correlated with clinical outcomes of ICH in the AML patients. We investigated the genetic mutations and clinical characteristics in the AML patients. We also detected the new fusion transcripts by the technique of next generation sequencing in the complex karyotype AML. We set up the basis of clinical characteristics and epidemiology of genetic mutations in the AML patients in Taiwan, and we hope these findings will be beneficial to the clinical management and improve the outcome in the adult patients with AML.
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