Meis1 is critical to the maintenance of human acute myeloid leukemia cells independent of MLL rearrangements
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Although the outcome of patients with acute myeloid leukemia (AML) has improved by optimized chemotherapy regimens and bone marrow transplantation, leukemia relapse remains one of the most challenging problems during therapy. Sustained existence of AML blasts is a fundamental determinant for the development of leukemia and resistance to therapy. Recent evidences suggest that Meis1 is tightly associated with the self-renewal capacity of normal hematopoietic stem cells. Meis1 was also found to be essential for the development of mixed lineage leukemia (MLL)-rearranged leukemia. Whether Meis1 functions independently of MLL abnormality in the context of leukemia is unclear. Herein, we identified a distinct expression pattern of Meis1 in patients with newly diagnosed AML without MLL abnormality. High levels of Meis1 expression were found in 64 of 95 (67.4%) AML patients; whereas, 31 of 95 (32.6%) patients showed dramatically lower levels of Meis1, compared with the median level of Meis1 in healthy donors. The whole cohort and subgroup analyses further demonstrated that high Meis1 expression levels were associated with a resistance to conventional chemotherapy, compared with the group with low Meis1 levels (P = 0.014 and P = 0.029, respectively). In vitro knockdown experiments highlighted a role of Meis1 in regulating maintenance and survival of human AML cells. These results implicate that Meis1 functions as an important regulator during the progression of human AML and could be a prognostic factor independent of MLL abnormality.
KeywordsAcute myeloid leukemia Meis1 MLL rearrangement Response to chemotherapy Maintenance
This study is supported by the Key Program of National Natural Science Foundation of China (Grant No. 81230013) and Scientific Research Foundation for Returned Scholars, Ministry of Education of China.
Compliance with ethical standards
All procedures were in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. The study protocols have been approved by the Ethical Committee of Peking University Institute of Hematology. All patients signed the consent forms.
Conflict of interest
The authors declare that they have no conflict of interest.
- 3.Huang XJ, Zhu HH, Chang YJ, Xu LP, Liu DH, Zhang XH, Jiang B, Jiang Q, Jiang H, Chen YH, Chen H, Han W, Liu KY, Wang Y (2012) The superiority of haploidentical related stem cell transplantation over chemotherapy alone as postremission treatment for patients with intermediate- or high-risk acute myeloid leukemia in first complete remission. Blood 119(23):5584–5590. doi: 10.1182/blood-2011-11-389809 CrossRefPubMedGoogle Scholar
- 9.Ariki R, Morikawa S, Mabuchi Y, Suzuki S, Nakatake M, Yoshioka K, Hidano S, Nakauchi H, Matsuzaki Y, Nakamura T, Goitsuka R (2014) Homeodomain transcription factor Meis1 is a critical regulator of adult bone marrow hematopoiesis. PLoS One 9(2):e87646. doi: 10.1371/journal.pone.0087646 CrossRefPubMedPubMedCentralGoogle Scholar
- 18.Zangenberg M, Grubach L, Aggerholm A, Silkjaer T, Juhl-Christensen C, Nyvold CG, Kjeldsen E, Ommen HB, Hokland P (2009) The combined expression of HOXA4 and MEIS1 is an independent prognostic factor in patients with AML. Eur J Haematol 83(5):439–448. doi: 10.1111/j.1600-0609.2009.01309.x CrossRefPubMedGoogle Scholar
- 21.Heuser M, Yun H, Berg T, Yung E, Argiropoulos B, Kuchenbauer F, Park G, Hamwi I, Palmqvist L, Lai CK, Leung M, Lin G, Chaturvedi A, Thakur BK, Iwasaki M, Bilenky M, Thiessen N, Robertson G, Hirst M, Kent D, Wilson NK, Gottgens B, Eaves C, Cleary ML, Marra M, Ganser A, Humphries RK (2011) Cell of origin in AML: susceptibility to MN1-induced transformation is regulated by the Meis1/AbdB-like Hox protein complex. Cancer Cell 20(1):39–52. doi: 10.1016/j.ccr.2011.06.020 CrossRefPubMedPubMedCentralGoogle Scholar
- 23.Argiropoulos B, Yung E, Xiang P, Lo CY, Kuchenbauer F, Palmqvist L, Reindl C, Heuser M, Sekulovic S, Rosten P, Muranyi A, Goh SL, Featherstone M, Humphries RK (2010) Linkage of the potent leukemogenic activity of Meis1 to cell-cycle entry and transcriptional regulation of cyclin D3. Blood 115(20):4071–4082. doi: 10.1182/blood-2009-06-225573 CrossRefPubMedGoogle Scholar
- 24.Bessa J, Tavares MJ, Santos J, Kikuta H, Laplante M, Becker TS, Gomez-Skarmeta JL, Casares F (2008) Meis1 regulates cyclin D1 and c-myc expression, and controls the proliferation of the multipotent cells in the early developing zebrafish eye. Development 135(5):799–803. doi: 10.1242/dev.011932 CrossRefPubMedGoogle Scholar
- 25.Riddell J, Gazit R, Garrison BS, Guo G, Saadatpour A, Mandal PK, Ebina W, Volchkov P, Yuan GC, Orkin SH, Rossi DJ (2014) Reprogramming committed murine blood cells to induced hematopoietic stem cells with defined factors. Cell 157(3):549–564. doi: 10.1016/j.cell.2014.04.006 CrossRefPubMedPubMedCentralGoogle Scholar