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Title: | 探討HOPX在血液系統及急性骨髓性白血病之角色 Explore the role of HOPX in hematopoietic system and acute myeloid leukemia. |
Authors: | Chien-Chin Lin 林建嶔 |
Advisor: | 周文堅 (Wen-Chien Chou) |
Keyword: | HOPX,白血病幹細胞,靜止態,CXCL12,CXCR4, HOPX,leukemia stem cell,quiescence,CXCL12,CXCR4, |
Publication Year : | 2020 |
Degree: | 博士 |
Abstract: | 急性骨髓性白血病是一個由血液前驅細胞所轉變成的癌症,是個進展快速且死亡率高的疾病;過去的研究指出具有白血病幹細胞特性者有更不好的預後。許多基因被報告與白血病幹細胞特性有關,其中一類很重要的是homeodomain家族的基因。HOPX是這家族中最小的一個蛋白,被發現在一些器官組織包括腸道、神經、肺泡、毛囊細胞是重要的幹細胞標記;也在許多實體癌症扮演抑癌基因的角色;然而其在造血系統的角色及功能尚不清楚。我們在研究的第一階段發現在急性骨髓性白血病的病人如果其白血病細胞的HOPX基因表現量高的人,其臨床特徵較具有白血病幹細胞特性以及靜止態特性。而為了探究HOPX在血液系統生理及病理上所扮演的角色,我們製造了一隻具有血液系統專一性Hopx基因剔除的小鼠(Hopx-/-)。這小鼠在年輕的時候,造血幹細胞在連續性的移植試驗會出現幹細胞再生能力下降的現象;進一步的轉錄組基因研究發現在年輕Hopx-/-小鼠的長期造血幹細胞會有'造血幹細胞基因印記特性'下降的情況。在18個月的時候,我們置放來長期觀察的六隻中有三隻出現'喪失造血幹細胞靜止特性的現象'。骨髓細胞的轉錄組基因分析發現Hopx-/-小鼠在Cxcl12-Cxcr4的這個徑路上有明顯的出現負調控的趨勢,而Cxcl12-Cxcr4的徑路對於維持造血幹細胞的靜止幹細胞特性目前已知扮演非常重要的角色。我們接著用MN1基因過度表達的方式去將小鼠的骨髓細胞轉化為急性骨髓性白血病細胞,如果是用Hopx-/-小鼠的造血細胞去轉化的,其表現型會較為侵襲性、分裂較快速,且Cxcl12-Cxcr4的這個徑路一樣是呈現負調控。於是我們進一步去測試病人的骨髓血漿CXCL12的濃度,發現到在低HOPX表現量的病人,其CXCL12的表現也較低。總結來說,我們的研究發現了HOPX在維持造血幹細胞靜止特性的重要,而且至少部分是經由CXCL12的路徑。 Acute myeloid leukemia (AML) is a malignancy of hematopoietic stem/progenitor cells (HSPC) with high mortality rate. A high expression of leukemia stem cell (LSC) character in AML predics poor prognosis and several genes have been reported to be associated with leukemia stemness, including several homeodomain genes. Homeodomain-only protein homeobox (HOPX) is by far the smallest homeodomain protein. Recently, it has been regarded as a stem cell marker in intestine, hair follicles, and pulmonary alveolar cells. Studies also suggested roles of HOPX as a tumor suppressor gene in various solid cancers. However its roles in hematopoietic cells and hematologic malignancies remains largely unknown. We analyzed the expression levels extracted from the mRNA array data derived from 347 newly diagnosed de novo acute myeloid leukemia patient cohort in the National Taiwan University Hospital (NTUH) and found that patients with higher HOPX expression had a lower complete remission rate and shorter survival. The finding was validated in two independent cohorts. Multivariate analysis revealed that higher HOPX expression was an independent unfavorable prognostic factor irrespective of other known prognostic parameters and gene signatures derived from multiple cohorts. Gene set enrichment analysis showed higher HOPX expression was associated with both hematopoietic and leukemia stem cell signatures. While HOPX and HOX family genes showed concordant expression patterns in normal HSPC, their expression patterns and associated clinical and biological features were distinctive in acute myeloid leukemia settings, demonstrating HOPX as a unique homeobox gene. To further explore the physiologic functions in hematopoietic system of HOPX, we generated a mouse model with hematopoietic cell-specific knockout of Hopx (Hopx-/-). In young Hopx-/- mice, the phenotypes were not distinct despite the transcriptomic study revealed decreased HSC signatures in long-term HSCs from the Hopx-/- mice. At 18 months of age, half of the Hopx-/- mice developed cytopenia and splenomegaly. Bone marrow (BM) from the sick mice showed phenotypes of loss of hematopoietic stem cell (HSC) quiescence. Transcriptomic study of the Hopx-/- marrow cells showed significant down-regulation of the Cxcl12-Cxcr4 axis, which is critical for maintenance of HSC quiescence. We next examined the role of Hopx in AML by using the MN1 overexpression murine leukemia model and found similar results. Furthermore, in human AML, BM plasma CXCL12 levels were lower in patients with lower HOPX expression. In summary, our study highlights the roles of Hopx in maintenance of quiescence of the hematopoietic stem cells through CXCL12 pathway in vivo and provides implication of this protein in normal and malignant hematopoiesis. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/52331 |
DOI: | 10.6342/NTU202100581 |
Fulltext Rights: | 有償授權 |
Appears in Collections: | 臨床醫學研究所 |
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