Journal of Genetics

, 98:35 | Cite as

Identification of an acute myeloid leukaemia associated noncoding somatic mutation at 3\(^\prime \) end of HOXA cluster

  • Xin XuEmail author
  • Lei Song
  • Yao Zhao
  • Lin Wang
  • Xinjing Zhang
  • Zhenming Shen
  • Chunling Zhao
  • Zhenbo HuEmail author
Research Note


Noncoding somatic mutations have been demonstrated to play important role in tumourigenesis. Here we show that there exists an acute myeloid leukaemia associated noncoding somatic mutation at 3\(^\prime \) terminal of conserved HOXA cluster. The mutation was identified in the bone marrow blasts but not peripheral blood mononuclear cells or buccal cells of two M3 (acute promyelocytic leukaemia, APL) type patients from 45 acute myeloid leukaemia patients. The mutation also existed in a pair of twins one of them developed acute myeloid leukaemia M4 (acute myelomonocytic leukaemia) type. The mutation resides in about 2-kb downstream of HOXA1 gene where a functional retinoic acid response element is located and also bound by histone demethylase KDM3B. Reporter assay showed that the mutation results in the upregulation of transcriptional activity and unresponsiveness to retinoic acid receptor. To sum up, we identified a new acute myeloid leukaemia associated noncoding somatic mutation.


acute myeloid leukaemia noncoding somatic mutation HOXA cluster 



This research was funded by the National Natural Science Foundation of China (NSFC) grant #81370628 and #81570157. Xin Xu was funded by the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry, Shandong Provincial Natural Science Foundation, China (#ZR2015CL023), Shandong Province Higher Educational Science and Technology Program (J16LL54), Weifang City Science and Technology Project 2018GX079. Lin Wang was funded by Weifang City Science and Technology Project (2015GX019). Chunling Zhao was funded by NSFC grant #81572578 and Shandong Provincial Natural Science Foundation, China #ZR2015HM028.


  1. Abate-Shen C. 2002 Deregulated homeobox gene expression in cancer: cause or consequence? Nat. Rev. Cancer 2, 777–785.CrossRefGoogle Scholar
  2. Alharbi R. A., Pettengell R., Pandha H. S. and Morgan R. 2013 The role of HOX genes in normal hematopoiesis and acute leukemia. Leukemia 27, 1000–1008.CrossRefGoogle Scholar
  3. Argiropoulos B. and Humphries R. K. 2007 Hox genes in hematopoiesis and leukemogenesis. Oncogene 26, 6766–6776.CrossRefGoogle Scholar
  4. De Kumar B. and Krumlauf R. 2016 HOXs and lincRNAs: two sides of the same coin. Sci. Adv. 2, e1501402.CrossRefGoogle Scholar
  5. Diederichs S., Bartsch L., Berkmann J. C., Fröse K., Heitmann J., Hoppe C. et al. 2016 The dark matter of the cancer genome: aberrations in regulatory elements, untranslated regions, splice sites, non-coding RNA and synonymous mutations. EMBO Mol. Med. 8, 442–457.CrossRefGoogle Scholar
  6. Ding L., Ley T. J., Larson D. E., Miller C. A., Koboldt D. C., Welch J. S. et al. 2012 Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature 481, 506–510.CrossRefGoogle Scholar
  7. Dupé V., Davenne M., Brocard J., Dollé P., Mark M., Dierich A. et al. 1997 In vivo functional analysis of the Hoxa-1 \(3^{\prime }\) retinoic acid response element (\(3^{\prime }\) RARE). Development 410, 399–410.Google Scholar
  8. Faber J., Krivtsov A. V., Stubbs M. C., Wright R., Davis T. N., Van Heuvel-Eibrink M. et al. 2009 HOXA9 is required for survival in human MLL-rearranged acute leukemias. Blood 113, 2375–2385.CrossRefGoogle Scholar
  9. Ghannam G., Takeda A., Camarata T., Moore M. A., Viale A. and Yaseen N. R. 2004 The oncogene Nup98-HOXA9 induces gene transcription in myeloid cells. J. Biol. Chem. 279, 866–875.CrossRefGoogle Scholar
  10. Golub T. R. 1999 Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 286, 531–537.CrossRefGoogle Scholar
  11. Khurana E., Fu Y., Chakravarty D., Demichelis F., Rubin M. A. and Gerstein M. 2016 Role of non-coding sequence variants in cancer. Nat. Rev. Genet. 17, 93–108.CrossRefGoogle Scholar
  12. Kolm P. J. and Sive H. L. 1995 Regulation of the Xenopus labial homeodomain genes, HoxA1 and HoxD1: activation by retinoids and peptide growth factors. Dev. Biol. 167, 34–49.CrossRefGoogle Scholar
  13. Thompson J. R., Chen S. W., Ho L., Langston A. W. and Gudas L. J. 1998 An evolutionary conserved element is essential for somite and adjacent mesenchymal expression of the Hoxa1 gene. Dev. Dyn. 211, 97–108.CrossRefGoogle Scholar
  14. Xu X., Nagel S., Quentmeier H., Wang Z., Pommerenke C., Dirks W. G. et al. 2018 KDM3B shows tumor-suppressive activity and transcriptionally regulates HOXA1 through retinoic acid response elements in acute myeloid leukemia. Leuk. Lymphoma 59, 204–213.CrossRefGoogle Scholar
  15. Xu X., Ren X., Wang H., Zhao Y., Yi Z., Wang K. et al. 2016 Identification and functional analysis of acute myeloid leukemia susceptibility associated single nucleotide polymorphisms at non-protein coding regions of RUNX1. Leuk. Lymphoma 57, 1442–1449.CrossRefGoogle Scholar

Copyright information

© Indian Academy of Sciences 2019

Authors and Affiliations

  1. 1.Laboratory for Stem Cell and Regenerative Medicinethe Affiliated Hospital of Weifang Medical UniversityWeifangPeople’s Republic of China
  2. 2.College of Bioscience and TechnologyWeifang Medical UniversityWeifangPeople’s Republic of China
  3. 3.The School of Physics and Optoelectronic EngineeringWeifang UniversityWeifangPeople’s Republic of China

Personalised recommendations