Microenvironment determines lineage fate in a human model of MLL-AF9 leukemia (Cancer Cell, 2008, 13:483-495)

報告日期: 2008/11/14
報告時間: 17:10/18:00
報告學生: 楊明哲
講評老師: 賴明德
附件下載:

http://basicmed.med.ncku.edu.tw/admin/up_img/971114-3.pdf

Microenvironment Determines Lineage Fate in a Human Model of MLL-AF9 Leukemia

Junping Wei, Mark Wunderlich, Catherine Fox, Sara Alvarez, Juan C. Cigudosa, Jamie S. Wilhelm,

Yi Zheng,Jose A. Cancelas,Yi Gu, Michael Jansen, Jorge F. DiMartino, and James C. Mulloy

Cancer Cell 13, 483–495, June 2008

 

SpeakerYoung Ming-Jer 楊明哲

CommentatorProf. Lai Ming-Derg 賴明德教授

Date : 14 November, 2008 (17:00~18:00)

Place : Room 602

 

Abstract :

 

As its name implies, the mixed-lineage leukemia (MLL) gene on chromosome 11q23 is rearranged in both acute myeloid and acute lymphoid leukemia (AML and ALL). While AML has been successfully produced in mice, modeling ALL has been more difficult. However, the nature of the leukemic stem cell (LSC) and the influence of environmental cues in MLL-associated leukemias are poorly understood. The authors used MA9 cells — CD34+ human cord blood (CB) cells transduced with an MLL–AF9 construct — and showed that they are immortal and can be cultured to assume either myeloid or lymphoid phenotypes, highlighting the contribution of culture conditions in lineage determination. When injected into non-obese diabetic, severe combined immunodeficient (NS) mice, MA9 cells led to the development of both AML and ALL. However, the introduction of MA9 cells into transgenic NS mice that express the human cytokines stem cell factor, granulocyte-macrophage colony-stimulating factor and interleukin 3 not only biased the disease towards a myeloid phenotype, but resulted in a more aggressive disease, further reinforcing the role of the cytokine milieu in specifying lineage. To further understand the nature of the LSC in MLL–AF9 leukemia, myeloid and lymphoid lines derived from a single CB transduction were injected into β2-globulin-deficient NS mice, triggering the development of AML and ALL respectively. Intriguingly, clonal identity was confirmed between at least one case of AML and ALL, implying that an LSC can be multipotent and can promote expansion of both myeloid and lymphoid lineages, and the subsequent development of two phenotypically diverse diseases. However, further experiments established that lineage-restricted LSCs can also be targets for MLL–AF9, thus demonstrating heterogeneity within LSCs in mixed-lineage leukemia. The ability of murine LSCs to emulate the human disease has always been uncertain, so how closely did these experimental leukemias recapitulate human MLL primary leukemias? A microarray-based approach revealed striking parallels between the transcriptional profiles of MA9 cells and those of leukaemic cells from AML patients with MLL fusions. Having established the validity of their murine model system, the authors sought to identify signaling pathways downstream of MLL fusion proteins. The small GTPase Rac was an obvious candidate, having been identified in a recent study as being hyperactivated in murine MA9 cells. Accordingly, the authors showed that inhibition of Rac in MA9 cells using short hairpin RNA or a small-molecule inhibitor resulted in cell cycle arrest and apoptosis, with a concomitant increase in BCL-XL degradation. Based on these observations, the authors assert that Rac may be an important therapeutic target for the treatment of MLL–AF9 leukemia. Patients with an MLL-AF9 fusion have an intermediate to poor prognosis, suggesting that MLL-AF9 expression is associated with a more aggressive disease that includes resistance to chemotherapy. This human-based system should prove useful in addressing the lineage promiscuity of MLL leukemias and allow testing of different therapeutic strategies.

 

References :

 

1.     Muntean A.G. , Hess J.L. MLL-AF9 Leukemia Stem Cells: Hardwired or Taking Cues from the Microenvironment? Cancer Cell 13, 465-466, 2008.

2.     Krivtsov A.V., Armstrong S.A. MLL translocations, histone modifications and leukaemia stem-cell development. Nature Review Cancer 7, 823-833, 2007.

3.     Huntly B.J.P., Gilliland D.G. Leukaemia stem cells and the evolution of cancer-stem-cell research. Nature Review Cancer 5, 311-321, 2005.