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Conference Paper: Tumor suppressive role of BMI-1 through inhibition of JAK-STAT signaling in leukemia
Title | Tumor suppressive role of BMI-1 through inhibition of JAK-STAT signaling in leukemia |
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Authors | |
Issue Date | 2017 |
Publisher | American Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/ |
Citation | Proceedings of the 108th Annual Meeting of the American Association for Cancer Research (AACR 2017), Washington, DC, USA, 1-5 April 2017. In Cancer Research, 2017, v. 77 n. 13, Suppl., p. abstract no. 5526 How to Cite? |
Abstract | BMI-1, which is one of the core components of polycomb repressive complex 1, is frequently found deregulated in patients with hematological disorders. In last decades, researchers concordantly agree that BMI-1 mediates tumorigenesis of leukemia stem cells through p16INK4A leukemogenic pathway. However, accumulating evidences contradict the idea that BMI-1 solely plays an oncogenic role in tumorigenesis. It has been shown BMI-1 depletion favors the development of myelofibrosis in mice; whereas high BMI-1 expression suppressed colony forming ability of MLL-ENL-transformed bone marrow and correlated with higher survival in some cancers. In this study, we hypothesized that BMI-1 plays a tumor suppressive role, which is independent of the regulation of INK4A-ARF locus, in human leukemia. BMI-1 was over-expressed in a panel of myeloid and lymphoid lineage leukemia cells, including HL-60, MV4-11, MonoMac-6, SEM, Nalm-20 and RS4;11. We observed no deregulation of p16INK4A and p14ARF genes by BMI-1, suggesting the regulation of INK4A-ARF locus is independent of BMI-1 modulation in leukemia cells. Nevertheless, over-expression of BMI-1 resulted in significant reduction of leukemia cell proliferation. It is noted that constitutively active JAK-STAT signaling pathway is crucial to leukemia cell survival. By modulation of BMI-1 level, we demonstrated suppression of the activated JAK-STAT signaling pathway in most of the leukemia cell lines with the exception of MonoMac-6 and RS4;11. This is in agreement with the high sensitivity to ruxolitinib, a JAK-STAT inhibitor, in all the tested leukemia cell lines except RS4;11. Importantly, we showed that BMI-1 over-expression could sensitize RS4;11 cells to reduce cell proliferation under ruxolitinib treatment. These results suggest that higher efficacy of ruxolitinib treatment could be achieved under a condition of high cellular level of BMI-1. We further demonstrated that ruxolitinib treatment was more effective in a cohort of AML patient samples (n = 25) with a context of higher BMI-1 expression (p < 0.05). Altogether, our results suggest that BMI-1 functions as a tumor suppressor gene via inhibition of the JAK-STAT signaling pathway. The endogenous level of BMI-1 could be served as an indicator for the effective treatment of JAK-STAT-dependent leukemia cells using ruxolitinib. |
Persistent Identifier | http://hdl.handle.net/10722/240884 |
ISSN | 2023 Impact Factor: 12.5 2023 SCImago Journal Rankings: 3.468 |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Lam, YM | - |
dc.contributor.author | Lam, SY | - |
dc.contributor.author | Leung, AYH | - |
dc.contributor.author | Ng, RK | - |
dc.date.accessioned | 2017-05-22T09:18:50Z | - |
dc.date.available | 2017-05-22T09:18:50Z | - |
dc.date.issued | 2017 | - |
dc.identifier.citation | Proceedings of the 108th Annual Meeting of the American Association for Cancer Research (AACR 2017), Washington, DC, USA, 1-5 April 2017. In Cancer Research, 2017, v. 77 n. 13, Suppl., p. abstract no. 5526 | - |
dc.identifier.issn | 0008-5472 | - |
dc.identifier.uri | http://hdl.handle.net/10722/240884 | - |
dc.description.abstract | BMI-1, which is one of the core components of polycomb repressive complex 1, is frequently found deregulated in patients with hematological disorders. In last decades, researchers concordantly agree that BMI-1 mediates tumorigenesis of leukemia stem cells through p16INK4A leukemogenic pathway. However, accumulating evidences contradict the idea that BMI-1 solely plays an oncogenic role in tumorigenesis. It has been shown BMI-1 depletion favors the development of myelofibrosis in mice; whereas high BMI-1 expression suppressed colony forming ability of MLL-ENL-transformed bone marrow and correlated with higher survival in some cancers. In this study, we hypothesized that BMI-1 plays a tumor suppressive role, which is independent of the regulation of INK4A-ARF locus, in human leukemia. BMI-1 was over-expressed in a panel of myeloid and lymphoid lineage leukemia cells, including HL-60, MV4-11, MonoMac-6, SEM, Nalm-20 and RS4;11. We observed no deregulation of p16INK4A and p14ARF genes by BMI-1, suggesting the regulation of INK4A-ARF locus is independent of BMI-1 modulation in leukemia cells. Nevertheless, over-expression of BMI-1 resulted in significant reduction of leukemia cell proliferation. It is noted that constitutively active JAK-STAT signaling pathway is crucial to leukemia cell survival. By modulation of BMI-1 level, we demonstrated suppression of the activated JAK-STAT signaling pathway in most of the leukemia cell lines with the exception of MonoMac-6 and RS4;11. This is in agreement with the high sensitivity to ruxolitinib, a JAK-STAT inhibitor, in all the tested leukemia cell lines except RS4;11. Importantly, we showed that BMI-1 over-expression could sensitize RS4;11 cells to reduce cell proliferation under ruxolitinib treatment. These results suggest that higher efficacy of ruxolitinib treatment could be achieved under a condition of high cellular level of BMI-1. We further demonstrated that ruxolitinib treatment was more effective in a cohort of AML patient samples (n = 25) with a context of higher BMI-1 expression (p < 0.05). Altogether, our results suggest that BMI-1 functions as a tumor suppressor gene via inhibition of the JAK-STAT signaling pathway. The endogenous level of BMI-1 could be served as an indicator for the effective treatment of JAK-STAT-dependent leukemia cells using ruxolitinib. | - |
dc.language | eng | - |
dc.publisher | American Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/ | - |
dc.relation.ispartof | Cancer Research | - |
dc.title | Tumor suppressive role of BMI-1 through inhibition of JAK-STAT signaling in leukemia | - |
dc.type | Conference_Paper | - |
dc.identifier.email | Lam, YM: simonyuk@hku.hk | - |
dc.identifier.email | Leung, AYH: ayhleung@hku.hk | - |
dc.identifier.email | Ng, RK: raykitng@hku.hk | - |
dc.identifier.authority | Leung, AYH=rp00265 | - |
dc.identifier.authority | Ng, RK=rp00273 | - |
dc.identifier.doi | 10.1158/1538-7445.AM2017-5526 | - |
dc.identifier.hkuros | 272364 | - |
dc.identifier.volume | 77 | - |
dc.identifier.issue | 13, Suppl. | - |
dc.identifier.spage | abstract no. 5526 | - |
dc.identifier.epage | abstract no. 5526 | - |
dc.identifier.isi | WOS:000442513305144 | - |
dc.publisher.place | United States | - |
dc.identifier.issnl | 0008-5472 | - |