INHIBITION OF LIN28B IMPAIRS LEUKEMIA CELL GROWTH AND METABOLISM IN ACUTE MYELOID LEUKEMIA
(Abstract release date: 05/18/17)
EHA Library. Zhou J. 05/18/17; 182365; PB1651
Dr. Jianbiao Zhou
Contributions
Contributions
Abstract
Abstract: PB1651
Type: Publication Only
Background
1. Current conventional chemotherapy for acute myeloid leukemia (AML) can achieve remission in over 70% of patients, but a majority of them will relapse within 5 years despite continued treatment.
2. The relapse is postulated to be due to leukemia stem cells (LSCs), which is different from normal hematopoietic stem cells (HSCs). LIN28B is microRNA regulator and stem cell reprogramming factor.
3. Overexpression of LIN28B has been associated with advance human malignancies and cancer stem cells (CSCs), including AML. However, the molecular mechanism by which LIN28B contributes to the development of AML remains largely elusive.
Aims
1. To study the function role of LIN28B in cell proliferation, cell cycle and colony formation ability of AML cells.
2. To systematically dissect transcriptional signalling mediated by LIN28B on whole genome level.
3. To determine the key targets of LIN28B in AML.
4. To explore the function of LIN28B in AML in vivo.
Methods
1. We modulated LIN28B expression in AML and non-leukemic cells and investigated functional consequences in cell proliferation, cell cycle and colony forming assays.
2. We performed a microarray-based analysis for LIN28B-silencing cells and interrogated gene expression data with different bioinformatic tools.
3. AML mouse xenograft model was used to examine the in vivo function of LIN28B.
Results
We first showed that increased LIN28B expression was associated with worse survival in AML patients. We demonstrated that targeting LIN28B in AML cells resulted in cell cycle arrest, inhibition of cell proliferation and colony formation, which was induced by de-repression of let-7a miRNA. On the other hand, overexpression of LIN28B promoted cell proliferation. Mechanistic studies revealed that inhibition of LIN28B induces metabolic changes in AML cells. IGF2BP1 was confirmed to be a novel downstream target of LIN28B via let-7 miRNA in AML. Notably, silencing LIN28B led to slow tumor growth in vivo.
Conclusion
In conclusion, these results uncover a novel mechanism of an important regulatory signaling, LIN28B/let-7/IGF2BP1, in leukemogenesis and provide a rationale to target this pathway as effective therapeutic strategy.
Session topic: 3. Acute myeloid leukemia - Biology
Keyword(s): Leukemogenesis, Acute Myeloid Leukemia, Stem and progenitor cell
Abstract: PB1651
Type: Publication Only
Background
1. Current conventional chemotherapy for acute myeloid leukemia (AML) can achieve remission in over 70% of patients, but a majority of them will relapse within 5 years despite continued treatment.
2. The relapse is postulated to be due to leukemia stem cells (LSCs), which is different from normal hematopoietic stem cells (HSCs). LIN28B is microRNA regulator and stem cell reprogramming factor.
3. Overexpression of LIN28B has been associated with advance human malignancies and cancer stem cells (CSCs), including AML. However, the molecular mechanism by which LIN28B contributes to the development of AML remains largely elusive.
Aims
1. To study the function role of LIN28B in cell proliferation, cell cycle and colony formation ability of AML cells.
2. To systematically dissect transcriptional signalling mediated by LIN28B on whole genome level.
3. To determine the key targets of LIN28B in AML.
4. To explore the function of LIN28B in AML in vivo.
Methods
1. We modulated LIN28B expression in AML and non-leukemic cells and investigated functional consequences in cell proliferation, cell cycle and colony forming assays.
2. We performed a microarray-based analysis for LIN28B-silencing cells and interrogated gene expression data with different bioinformatic tools.
3. AML mouse xenograft model was used to examine the in vivo function of LIN28B.
Results
We first showed that increased LIN28B expression was associated with worse survival in AML patients. We demonstrated that targeting LIN28B in AML cells resulted in cell cycle arrest, inhibition of cell proliferation and colony formation, which was induced by de-repression of let-7a miRNA. On the other hand, overexpression of LIN28B promoted cell proliferation. Mechanistic studies revealed that inhibition of LIN28B induces metabolic changes in AML cells. IGF2BP1 was confirmed to be a novel downstream target of LIN28B via let-7 miRNA in AML. Notably, silencing LIN28B led to slow tumor growth in vivo.
Conclusion
In conclusion, these results uncover a novel mechanism of an important regulatory signaling, LIN28B/let-7/IGF2BP1, in leukemogenesis and provide a rationale to target this pathway as effective therapeutic strategy.
Session topic: 3. Acute myeloid leukemia - Biology
Keyword(s): Leukemogenesis, Acute Myeloid Leukemia, Stem and progenitor cell
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