Original Article | Published:

Acute lymphoblastic leukemia

Expression of the fetal hematopoiesis regulator FEV indicates leukemias of prenatal origin

Leukemia volume 31, pages 10791086 (2017) | Download Citation

Abstract

The origin of cancers is associated with etiology as well as therapeutics. Several studies reveal that malignancies in children can originate in utero. However, a diagnostic approach to distinguish between cancers initiated pre- or postnatally is absent. Here we identified a transcriptional factor FEV (fifth Ewing variant) that was expressed in fetal hematopoietic cells and became silent after birth. We characterized that FEV was essential for the self-renewal of hematopoietic stem cells (HSCs). We next found that FEV was expressed in most infant leukemia samples, but seldom in adult samples, in accord with the known prenatal origins of the former. We further determined the majority of pediatric acute lymphoid leukemia (ALL) and acute myeloid leukemia (AML) were FEV positive. Moreover, FEV knockdown markedly impaired the leukemia-propagating ability of leukemic stem cells. We therefore identified FEV is unique to fetal HSCs and stably expressed in leukemic cells of prenatal origin. It may also provide a tractable therapeutic target.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    . Congenitales, quergestreiftes Muskelsarkom der Nieren. Virchows Arch 1875; 65: 64–69.

  2. 2.

    . Nesso fisio-patologico tra la struttura dei nei materni e la genesi di alcuni tumori maligni. Arch Memo Observ Chir Prat 1874; 11: 217–226.

  3. 3.

    . Die multiloculäre, ulcerirende Echinokokkengeschwulst der Leber. Verhandlungen der Physicalisch-Medicinischen Gesellschaft 1855; 6: 84–95.

  4. 4.

    , , , , , et al. In utero rearrangements in the trithorax-related oncogene in infant leukaemias. Nature 1993; 363: 358–360.

  5. 5.

    , , , , , et al. Prenatal origin of acute lymphoblastic leukaemia in children. Lancet 1999; 354: 1499–1503.

  6. 6.

    , , , , , et al. Detection of clonotypic IGH and TCR rearrangements in the neonatal blood spots of infants and children with B-cell precursor acute lymphoblastic leukemia. Blood 2000; 96: 264–268.

  7. 7.

    , , , , , et al. In utero origin of t(8;21) AML1-ETO translocations in childhood acute myeloid leukemia. Blood 2002; 99: 3801–3805.

  8. 8.

    , , , , , et al. Human fetal neuroblast and neuroblastoma transcriptome analysis confirms neuroblast origin and highlights neuroblastoma candidate genes. Genome Biol 2006; 7: R84.

  9. 9.

    , , , , , et al. Developmental defects in Gorlin syndrome related to a putative tumor suppressor gene on chromosome 9. Cell 1992; 69: 111–117.

  10. 10.

    , , , , , . Cell-specific effects of RB or RB/p107 loss on retinal development implicate an intrinsically death-resistant cell-of-origin in retinoblastoma. Cancer Cell 2004; 5: 539–551.

  11. 11.

    , , , , , et al. Initiating and cancer-propagating cells in TEL-AML1-associated childhood leukemia. Science 2008; 319: 336–339.

  12. 12.

    , , , , , et al. The prenatal origins of cancer. Nat Rev Cancer 2014; 14: 277–289.

  13. 13.

    , . Origins of chromosome translocations in childhood leukaemia. Nat Rev Cancer 2003; 3: 639–649.

  14. 14.

    , , , , , et al. A new member of the ETS family fused to EWS in Ewing tumors. Oncogene 1997; 14: 1159–1164.

  15. 15.

    , . Genome-wide analysis of the zebrafish ETS family identifies three genes required for hemangioblast differentiation or angiogenesis. Circ Res 2008; 103: 1147–1154.

  16. 16.

    , , , , , et al. Fev regulates hematopoietic stem cell development via ERK signaling. Blood 2013; 122: 367–375.

  17. 17.

    , , , , , et al. Standardization and quality control studies of 'real-time' quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia - a Europe Against Cancer program. Leukemia 2003; 17: 2318–2357.

  18. 18.

    , , , , . The use of housekeeping genes for real-time PCR-based quantification of fusion gene transcripts in acute myeloid leukemia. Leukemia 2004; 18: 1551–1553.

  19. 19.

    , , , , , et al. Stem cell programs are retained in human leukemic lymphoblasts. Oncogene 2015; 34: 2083–2093.

  20. 20.

    , , , , . NOV (CCN3) functions as a regulator of human hematopoietic stem or progenitor cells. Science 2007; 316: 590–593.

  21. 21.

    , , , , , et al. Leukemia propagating cells rebuild an evolving niche in response to therapy. Cancer Cell 2014; 25: 778–793.

  22. 22.

    , , , , , et al. Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia. Cancer Cell 2011; 19: 138–152.

  23. 23.

    , , , , , . Isolation of single human hematopoietic stem cells capable of long-term multilineage engraftment. Science 2011; 333: 218–221.

  24. 24.

    , , , , , et al. Stem cell gene expression programs influence clinical outcome in human leukemia. Nat Med 2011; 17: 1086–1093.

  25. 25.

    , . Differential contributions of haematopoietic stem cells to foetal and adult haematopoiesis: insights from functional analysis of transcriptional regulators. Oncogene 2007; 26: 6750–6765.

  26. 26.

    . Intrinsic and extrinsic control of haematopoietic stem-cell self-renewal. Nature 2008; 453: 306–313.

  27. 27.

    , , , . Leukemia in twins: lessons in natural history. Blood 2003; 102: 2321–2333.

  28. 28.

    , , , , , et al. Genetic variegation of clonal architecture and propagating cells in leukaemia. Nature 2011; 469: 356–361.

  29. 29.

    , , , , , et al. CD34+CD38+CD19+ as well as CD34+CD38-CD19+ cells are leukemia-initiating cells with self-renewal capacity in human B-precursor ALL. Leukemia 2008; 22: 1207–1213.

  30. 30.

    , , , , , et al. In childhood acute lymphoblastic leukemia, blasts at different stages of immunophenotypic maturation have stem cell properties. Cancer Cell 2008; 14: 47–58.

  31. 31.

    , , , , , . Fetal origins of the TEL-AML1 fusion gene in identical twins with leukemia. Proc Natl Acad Sci USA 1998; 95: 4584–4588.

  32. 32.

    , , , , , et al. Presence of clone-specific markers at birth in children with acute lymphoblastic leukaemia. Br J Cancer 2002; 87: 994–999.

  33. 33.

    , , , , , et al. High frequency of leukemic clones in newborn screening blood samples of children with B-precursor acute lymphoblastic leukemia. Blood 2002; 99: 2992–2996.

  34. 34.

    , , , , , et al. Backtracking leukemia to birth: identification of clonotypic gene fusion sequences in neonatal blood spots. Proc Natl Acad Sci USA 1997; 94: 13950–13954.

  35. 35.

    , , . Tracking down the origin of stem cell programs in cancer cells. Ann Hematol Oncol 2015; 2: 1054–1055.

  36. 36.

    , , , , , et al. Presence of N regions in the clonotypic DJ rearrangements of the immunoglobulin heavy-chain genes indicates an exquisitely short latency in t(4;11)-positive infant acute lymphoblastic leukemia. Blood 2001; 98: 2272–2274.

  37. 37.

    , , , , , . Protracted postnatal natural histories in childhood leukemia. Genes Chromosomes Cancer 2004; 39: 335–340.

Download references

Acknowledgements

We thank M Greaves for critical comments on the paper. We thank B Zhang for the provision of fev:GFP zebrafish. B Zhao and C Duan are also acknowledged for their technical assistance in flow-sorting and mouse injection, respectively. This work was supported by grants from the National Basic Research Program of China (Grant No. 2012CB967001 to D-LH and 2010CB945300 and 2011CB943900 to FL) and the National Natural Science Foundation of China (Grant Nos. 81120108006, 90919055 and 91442106 to D-LH and 31425016 to FL).

Author contributions

T-HL designed and performed the experiments and analyzed the results; Y-JT and T-HL collected and analyzed the clinical data; LW and FL performed zebrafish experiments; YH and Q-JY collected human fetal liver and BM cells; X-LG, YZ, LC, HZ, XL and L-HZ collected human CB cells; J-YT, B-SL, J-QM and L-GL collected patient samples and related clinical information; AF detected FEV expression and analyzed data; TE, FL and G-QC discussed the data and contributed to the writing of the manuscript; D-LH supervised the project, designed the experiments and wrote the paper.

Author information

Author notes

    • T-H Liu
    • , Y-J Tang
    • , Y Huang
    •  & L Wang

    These authors contributed equally to this work.

Affiliations

  1. Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Department of Pathophysiology and Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China

    • T-H Liu
    • , Y Huang
    • , X-L Guo
    • , Q-J Ye
    • , G-Q Chen
    •  & D-L Hong
  2. Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Department of Hematology and Oncology, Shanghai Children’s Medical Center, SJTU-SM, Shanghai, China

    • Y-J Tang
    • , B-S Li
    •  & J-Y Tang
  3. State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China

    • L Wang
    •  & F Liu
  4. Shanghai Institute of Hematology, Ruijin Hospital, SJTU-SM, Shanghai, China

    • J-Q Mi
  5. Hematological Department, The Fifth People’s Hospital of Shanghai, Fudan University, Shanghai, China

    • L-G Liu
  6. Shanghai Cord Blood Bank, Shanghai, China

    • H Zhu
    • , Y Zhang
    •  & L Chen
  7. Huangshi Love Health Hospital, Huangshi, China

    • X Liu
    •  & L-H Zhang
  8. Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK

    • A Ford
  9. Stem Cell Laboratory, UCL Cancer Institute, University College London, London, UK

    • T Enver

Authors

  1. Search for T-H Liu in:

  2. Search for Y-J Tang in:

  3. Search for Y Huang in:

  4. Search for L Wang in:

  5. Search for X-L Guo in:

  6. Search for J-Q Mi in:

  7. Search for L-G Liu in:

  8. Search for H Zhu in:

  9. Search for Y Zhang in:

  10. Search for L Chen in:

  11. Search for X Liu in:

  12. Search for L-H Zhang in:

  13. Search for Q-J Ye in:

  14. Search for B-S Li in:

  15. Search for J-Y Tang in:

  16. Search for A Ford in:

  17. Search for T Enver in:

  18. Search for F Liu in:

  19. Search for G-Q Chen in:

  20. Search for D-L Hong in:

Competing interests

The authors declare no conflict of interest.

Corresponding authors

Correspondence to F Liu or G-Q Chen or D-L Hong.

Supplementary information

About this article

Publication history

Received

Revised

Accepted

Published

DOI

https://doi.org/10.1038/leu.2016.313

Supplementary Information accompanies this paper on the Leukemia website (http://www.nature.com/leu)