Annals of Hematology

, Volume 96, Issue 4, pp 567–574 | Cite as

Meis1 is critical to the maintenance of human acute myeloid leukemia cells independent of MLL rearrangements

  • Jiangying Liu
  • Ya-Zhen Qin
  • Shenmiao Yang
  • Yazhe Wang
  • Ying-Jun Chang
  • Ting Zhao
  • Qian Jiang
  • Xiao-Jun Huang
Original Article


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.


Acute 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.


  1. 1.
    Walter RB, Appelbaum FR, Tallman MS, Weiss NS, Larson RA, Estey EH (2010) Shortcomings in the clinical evaluation of new drugs: acute myeloid leukemia as paradigm. Blood 116(14):2420–2428. doi: 10.1182/blood-2010-05-285387 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Lutz C, Hoang VT, Buss E, Ho AD (2013) Identifying leukemia stem cells—is it feasible and does it matter? Cancer Lett 338(1):10–14. doi: 10.1016/j.canlet.2012.07.014 CrossRefPubMedGoogle Scholar
  3. 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
  4. 4.
    Orford KW, Scadden DT (2008) Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation. Nat Rev Genet 9(2):115–128. doi: 10.1038/nrg2269 CrossRefPubMedGoogle Scholar
  5. 5.
    Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70CrossRefPubMedGoogle Scholar
  6. 6.
    Look AT (1997) Oncogenic transcription factors in the human acute leukemias. Science 278(5340):1059–1064CrossRefPubMedGoogle Scholar
  7. 7.
    Moskow JJ, Bullrich F, Huebner K, Daar IO, Buchberg AM (1995) Meis1, a PBX1-related homeobox gene involved in myeloid leukemia in BXH-2 mice. Mol Cell Biol 15(10):5434–5443CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Moens CB, Selleri L (2006) Hox cofactors in vertebrate development. Dev Biol 291(2):193–206. doi: 10.1016/j.ydbio.2005.10.032 CrossRefPubMedGoogle Scholar
  9. 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
  10. 10.
    Unnisa Z, Clark JP, Roychoudhury J, Thomas E, Tessarollo L, Copeland NG, Jenkins NA, Grimes HL, Kumar AR (2012) Meis1 preserves hematopoietic stem cells in mice by limiting oxidative stress. Blood 120(25):4973–4981. doi: 10.1182/blood-2012-06-435800 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Kocabas F, Zheng J, Thet S, Copeland NG, Jenkins NA, DeBerardinis RJ, Zhang C, Sadek HA (2012) Meis1 regulates the metabolic phenotype and oxidant defense of hematopoietic stem cells. Blood 120(25):4963–4972. doi: 10.1182/blood-2012-05-432260 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Kumar AR, Li Q, Hudson WA, Chen W, Sam T, Yao Q, Lund EA, Wu B, Kowal BJ, Kersey JH (2009) A role for MEIS1 in MLL-fusion gene leukemia. Blood 113(8):1756–1758. doi: 10.1182/blood-2008-06-163287 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Wong P, Iwasaki M, Somervaille TC, So CW, Cleary ML (2007) Meis1 is an essential and rate-limiting regulator of MLL leukemia stem cell potential. Genes Dev 21(21):2762–2774. doi: 10.1101/gad.1602107 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Kumar AR, Sarver AL, Wu B, Kersey JH (2010) Meis1 maintains stemness signature in MLL-AF9 leukemia. Blood 115(17):3642–3643. doi: 10.1182/blood-2010-01-264564 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Quentmeier H, Dirks WG, Macleod RAF, Reinhardt J, Zaborski M, Drexler HG (2004) Expression of HOX genes in acute leukemia cell lines with and without MLL translocations. Leukemia & Lymphoma 45(3):567–574. doi: 10.1080/10428190310001609942 CrossRefGoogle Scholar
  16. 16.
    Afonja O, Smith JE Jr, Cheng DM, Goldenberg AS, Amorosi E, Shimamoto T, Nakamura S, Ohyashiki K, Ohyashiki J, Toyama K, Takeshita K (2000) MEIS1 and HOXA7 genes in human acute myeloid leukemia. Leuk Res 24(10):849–855CrossRefPubMedGoogle Scholar
  17. 17.
    Mahmoud AI, Kocabas F, Muralidhar SA, Kimura W, Koura AS, Thet S, Porrello ER, Sadek HA (2013) Meis1 regulates postnatal cardiomyocyte cell cycle arrest. Nature 497(7448):249–253. doi: 10.1038/nature12054 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 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
  19. 19.
    Lozzio CB, Lozzio BB (1975) Human chronic myelogenous leukemia cell-line with positive Philadelphia chromosome. Blood 45(3):321–3344PubMedGoogle Scholar
  20. 20.
    Ferrara F, Schiffer CA (2013) Acute myeloid leukaemia in adults. Lancet 381(9865):484–495. doi: 10.1016/S0140-6736(12)61727-9 CrossRefPubMedGoogle Scholar
  21. 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
  22. 22.
    Lawrence HJ, Rozenfeld S, Cruz C, Matsukuma K, Kwong A, Komuves L, Buchberg AM, Largman C (1999) Frequent co-expression of the HOXA9 and MEIS1 homeobox genes in human myeloid leukemias. Leukemia 13(12):1993–1999CrossRefPubMedGoogle Scholar
  23. 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. 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. 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
  26. 26.
    Wahlestedt M, Bryder D (2014) Induced hematopoietic stem cells: unlocking restrictions in lineage potential and self-renewal. Cell Stem Cell 14(5):555–556. doi: 10.1016/j.stem.2014.04.008 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Jiangying Liu
    • 1
  • Ya-Zhen Qin
    • 1
  • Shenmiao Yang
    • 1
  • Yazhe Wang
    • 1
  • Ying-Jun Chang
    • 1
  • Ting Zhao
    • 1
  • Qian Jiang
    • 1
  • Xiao-Jun Huang
    • 1
  1. 1.Peking University People’s Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell TransplantationBeijingChina

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