Crucial Role of BAALC-Expressing Progenitor Cells in Emergence and Development of Post-Transplantation Relapses in Patients with Acute Myeloid Leukemia

NN Mamaev, AI Shakirova, IM Barkhatov, YaV Gudozhnikova, TL Gindina, OV Paina, LS Zubarovskaya, BV Afanas’ev

RM Gorbacheva Scientific Research Institute of Pediatric Oncology, Hematology and Transplantation; IP Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

For correspondence: Prof. Nikolai Nikolaevich Mamaev, MD, PhD, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; e-mail:

For citation: Mamaev NN, Shakirova AI, Barkhatov IM, et al. Crucial Role of BAALCExpressing Progenitor Cells in Emergence and Development of Post-Transplantation Relapses in Patients with Acute Myeloid Leukemia. Clinical oncohematology. 2020;13(1):75–88 (In Russ).

DOI: 10.21320/2500-2139-2020-13-1-75-88


This article presents data demonstrating frequent BAALC hyperexpression, also in combination with WT1 hyperexpression, in children and adults with acute myeloid leukemia (AML). Treatment included allogeneic hematopoietic stem cell transplantation. The analysis of serial measurements of BAALC and WT1 expression level in 50 AML patients (37 adults and 13 children) showed that the increased BAALC expression is more common in patients with M1, M2, M4, and M5 FAB variants of AML with equal frequency in adults and children. Furthermore, the increased BAALC expression was rather common in combination with the increased WT1 expression, which predicted poorer prognosis. Since BAALC expression level in AML patients is closely related to AML-producing progenitor cells of leukemia hematopoiesis, a serial study of this phenomenon offers insights into the role of these cells in emergence and development of post-transplantation relapses, which is of both theoretical and practical importance.

Keywords: acute myeloid leukemia, BAALC and WT1 genes, synchronous hyperexpression, post-transplantation relapses, BAALCproducing progenitor cells, prognosis.

Received: June 30, 2019

Accepted: December 1, 2019

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  1. MacLean AL, Lo Celso C, Stumpf MPH. Stem cell population biology: Insights from hematopoiesis. Stem Cells. 2017;35(1):88–8. doi: 10.1002/stem.2508.

  2. Yilmaz OH, Valdez R, Theisen BK, et al. Pten dependence distinguishes haematopoietic stem cells from leukemia-initiating cells. Nature. 2006;441(25):475–82. doi: 10.1038/nature04703.

  3. Quek E, Otto GW, Garnett C, et al. Genertically distinct leukemic stem cells in human CD34 acute myeloid leukemia are arrested at a hematopoietic precursor-like stage. J Exp Med. 2016;213(8):1513–35. doi: 10.1084/jem.20151775.

  4. Brenet F, Scandura JM. Cutting the brakes on hematopoietic regeneration by blocking TGFβ to limit chemotherapy-induced myelosuppression. Mol Cell Oncol. 2015;2(3):e978703. doi: 10.4161/23723556.2014.978703.

  5. Riether C, Schurch CM, Ochsenbein AF. Regulation of hematopoietic and leukemic stem cells by the immune system. Cell Death Differ. 2015;22(2):187–98. doi: 10.1038/cdd.2014.89.

  6. Laurenti E, Gottgens B. From haematopoietic stem cells to complex differentiation landscapes. Nature. 2018;553(7689):418–26. doi: 10.1038/nature25022.

  7. Cilloni D, Renneville A, Hermitte F, et al. Real-time quantitative polymerase chain reaction detection of minimal residual disease by standardized WT1 assay to enhance risk stratification in acute myeloid leukemia: a European LeukemiaNet study. J Clin Oncol. 2009;27(31):5195–201. doi: 10.1200/JCO.2009.22.4865.

  8. Гудожникова Я.В., Мамаев Н.Н., Бархатов И.М. и др. Результаты молекулярного мониторинга в посттрансплантационный период с помощью серийного исследования уровня экспрессии гена WT1 у больных острыми миелоидными лейкозами. Клиническая онкогематология. 2018;11(3):241–51. doi: 10.21320/2500-2139-2018-11-3-241-251.

    [Gudozhnikova YaV, Mamaev NN, Barkhatov IM, et al. Results of Molecular Monitoring in Posttransplant Period by Means of Series Investigation of WT1 Gene Expression in Patients with Acute Myeloid Leukemia. Clinical oncohematology. 2018;11(3):241–51. doi: 10.21320/2500-2139-2018-11-3-241-251. (In Russ)]

  9. Won EJ, Kim H-R, Choi S-Y, et al. Direct confirmation of quiescence of CD34+Cd38- leukemia stem cell populations using single cell culture, their molecular signature and clinicopathological implications. BioMed Central Cancer. 2015;15(1):2017. doi: 10.1186/s12885-015-1233-x.

  10. Gerber JM, Smith BD, Ngwang B, et al. A clinically relevant population of leukemic CD34(+)CD38(-) cells in acute myeloid leukemia. Blood. 2012;119(15):3571–7. doi: 10.1182/blood-2011-06-364182.

  11. Gerber JM, Zeidner JF, Morse S, et al. Association of acute myeloid leukemia’s most immature phenotype with risk groups and outcomes. Haematologica. 2016;101(5):607–16. doi: 10.3324/haematol.2015.135194.

  12. Jentzsch M, Bill M, Nicolet D, et al. Prognostic impact of the CD34+/CD38- cell burden in patients with acute myeloid leukemia receiving allogeneic stem cell transplantation. Am J Hematol. 2017;92(4):388–96. doi: 10.1002/ajh.24663.

  13. Baldus CD, Tanner SM, Kusewitt DF, et al. BAALC, a novel marker of human hematopoietic progenitor cells. Exp Hematol. 2003; 31(11):1051–6. doi: 10.1016/j.exphem.2003.08.004.

  14. Rapin N, Bagger FO, Jendholm J, et al. Comparing cancer vs normal gene expression profiles identifies new disease entities and common transcriptional programs in AML patients. 2014;123(6):894–904. doi: 10.1182/blood-2013-02-485771.

  15. Morita K, Masamoto Y, Kataoka K, et al. BAALC potentiates oncogenic ERK pathway through interactions with MEKK1 and KLF4. Leukemia. 2015;29(11):2248–56. doi: 10.1038/leu.2015.137.

  16. Jentzsch M, Bill M, Grimm J, et al. High BAALC copy numbers in peripheral blood prior to allogeneic transplantation predict early relapse in acute myeloid leukemia patients. Oncotarget. 2017;8(50):87944–54. doi: 10.18632/oncotarget.21322.

  17. Tanner SM, Austin JL, Leone G, et al. BAALC, the human member of a novel mammalian neuroectoderm gene lineage, is implicated in hematopoiesis and acute leukemia. Proc Natl Acad Sci USA. 2001;98(24):13901–6. doi: 10.1073/pnas.241525498.

  18. Baldus CD, Tanner SM, Ruppert AS, et al. BAALC expression predicts clinical outcome of de novo acute myeloid leukemia patients with normal cytogenetics: a Cancer and Leukemia Group B Study. Blood. 2003;102(5):1613–8. doi: 10.1182/blood-2003-02-0359.

  19. Qi X, Shen Y, Cen J, et al. Up-regulation of BAALC gene may be an important alteration in AML-M2 patients with t(8;21) translocation. J Cell Mol Med. 2008;12(6A):2301–4. doi: 10.1111/j.1582-4934.2008.00447.x.

  20. Langer C, Radmacher MD, Ruppert AS, et al. High BAALC expression associates with other molecular prognostic markers, poor outcome, and a distinct gene-expression signature in cytogenetically normal patients younger than 60 years with acute myeloid leukemia: a Cancer and Leukemia Group B (CALGB) study. 2008;111:5371–9. doi: 10.1182/blood-2007-11-124958.

  21. Mizushima Y, Taki T, Shimada A, et al. Prognostic significance of the BAALC isoform pattern and CEBPA mutations in pediatric acute myeloid leukemia with normal karyotype: a study by the Japanese Childhood AML Cooperative Study Group. Int J Hematol. 2010;91(5):831–7. doi: 10.1007/s12185-010-0585-x.

  22. Yahya RS, Sofan MA, Abdelmasseih HM, et al. Prognostic implication of BAALC gene expression in adult acute myeloid leukemia. Clin Lab. 2013;59:621–8. doi: 7754/Clin.Lab.2012.120604.

  23. Becker H, Maharry K, Mrozek K, et al. Prognostic gene mutations and distinct gene- and microRNA-expression signatures in acute myeloid leukemia with a sole trisomy 8. Leukemia. 2014;28(8):1754–8. doi: 10.1038/leu.2014.114.

  24. Santamaria C, Chillon MC, Garcia-Sanz R, et al. BAALC is an important predictor of refractoriness to chemotherapy and poor survival in intermediate-risk acute myeloid leukemia (AML). Ann Hematol. 2010;89(5):453–8. doi: 10.1007/s00277-009-0864-x.

  25. Najima Y, Ohashi K, Kawamura M, et al. Molecular monitoring of BAALC expression in patients with CD34-positive acute leukemia. Int J Hematol. 2010;91(4):636–45. doi: 10.1007/s12185-010-0550-8.

  26. Staffas A, Kanduri M, Hovland R, et al. Nordic Society of Pediatric Hematology and Oncology (NOPHO). Presence of FLT3-ITD and high BAALC expression are independent prognostic markers in childhood acute myeloid leukemia. Blood. 2011;118(22):5905–13. doi: 10.1182/blood-2011-05-353185.

  27. Hirsch P, Tang R, Marzac C, et al. Prognostic impact of high ABC transporter activity in 111 adult acute myeloid leukemia patients with normal cytogenetics when compared to FLT3, NPM1, CEBPA and BAALC. Haematologica. 2012;97(2):241–5. doi: 10.3324/haematol.2010.034447.

  28. Haferlach C, Kern W, Schindela S, et al. Gene expression of BAALC, CDKN1B, ERG, and MN1 adds independent prognostic information to cytogenetics and molecular mutations in adult acute myeloid leukemia. Genes Chromosom 2012;51(3):257–65. doi: 10.1002/gcc.20950.

  29. Zhang J, Shi J, Zhang G, et al. BAALC and ERG expression levels at diagnosis have no prognosis impact on acute myeloid leukemia patients undergoing allogeneic hematopoietic stem cell transplantation. Ann Hematol. 2018;97(8):1391–7. doi: 10.1007/s00277-018-3331-8.

  30. Zhou JD, Yang L, Zhang YY, et al. Overexpression of BAALC: clinical significance in Chinese de novo acute myeloid leukemia. Med Oncol. 2015;32(1):386. doi: 10.1007/s12032-014-0386-9.

  31. Xiao SJ, Shen JZ, Huang JL, Fu HY. Prognostic significance of the BAALC gene expression in adult patients with acute myeloid leukemia: A meta-analysis. Mol Clin Oncol. 2015;3(4):880–8. doi: 10.3892/mco.2015.562.

  32. Weber S, Haferlach T, Alpermann T, et al. Feasibility of BAALC gene expression for detection of minimal residual disease and risk stratification in normal karyotype acute myeloid leukaemia. Br J Haematol. 2016;175(5):904–16. doi: 10.1111/bjh.14343.

  33. Shakirova A, Barkhatov I, Churkina A, et al. Prognostic significance of BAALC overexpression in patients with AML during the post-transplant period. Cell Ther Transplant. 2018;7(2):54–63. doi: 10.18620/ctt-1866-8836-2018-7-2-54-63.

  34. Pogosova-Agadjanyan E, Moseley A, Othus M, et al. Impact of specimen heterogeneity on biomarkers in repository samples from patients with acute myeloid leukemia: A SWOG report. Biopreserv Biobank. 2018;16(1):42–52. doi: 10.1089/bio.2017.0079.

  35. Eisfeld AK, Marcucci G, Liyanarachchi S, et al. Heritable polymorphism predisposes to high BAALC expression in acute myeloid leukemia. Proc Natl Acad Sci USA. 2012;109(17):6668–73. doi: 10.1073/pnas.1203756109.

  36. Nadimi M, Rahgozar S, Moafi A, et al. Evaluation of rs62527607 [GT] single nucleotide polymorphism located in BAALC gene in children with acute leukemia using mismatch PCR-RFLP. Cancer Genet. 2016;209(7–8):348–53. doi: 1016/j.cancergen.2016.06.005.

  37. Lam K, Zhang DE. RUNX1 and RUNX1-ETO: roles in hematopoiesis and leukemogenesis. Front Biosci. 2012;1(17):1120–39. doi: 10.2741/3977.

  38. Nolte F, Hecht A, Reinwald M, et al. In acute promyelocytic leukemia (APL) low BAALC gene expression identifies a patient group with favorable overall survival and improved relapse free survival. Leuk Res. 2013;37(4);378–82. doi: 10.1016/j.leukres.2012.

  39. Iljima N, Miyamura K, Itou T, et al. Functional expression of FAS (CD95) in acute myeloid leukemia cells in context of CD34 and CD38 expression: possible correlation with sensitivity to chemotherapy. Blood. 1997;90(12):4901–9. doi: 10.1182/blood.v90.12.4901.

  40. Ding Y, Gao H, Zhang Q. The biomarkers of leukemia stem cells in acute myeloid leukemia. Stem Cell Investig. 2017;4(3):19. doi: 10.21037/sci.2017.02.10.

  41. Yoon JH, Kim HJ, Shin SH, et al. BAALC and WT1 expressions from diagnosis to hematopoietic stem cell transplantation: consecutive monitoring in adult patients with core-binding-factor-positive AML. Eur J Haematol. 2013;91(2):112–21. doi: 10.1111/ejh.12142.

  42. Мамаев Н.Н., Горбунова А.В., Гиндина Т.Л. и др. Лейкозы и миелодиспластические синдромы с высокой экспрессией гена EVI1: теоретические и клинические аспекты. Клиническая онкогематология. 2012;5(4):361–4.

    [Mamaev NN, Gorbunova AV, Gindina TL, et al. Leukemias and myelodysplastic syndromes with high EVI1 gene expression: theoretical and clinical aspects. Klinicheskaya onkogematologiya. 2012;5(4):361–4. (In Russ)]

  43. Hermkens MCH, van den Heuvel-Eibrink MM, Arentsen-Peters STCJM, et al. The clinical relevance of BAALC and ERG expression levels in pediatric AML. Leukemia. 2013;27(3):735–7. doi: 1038/leu.2012.233.

  44. Minetto P, Guolo F, Clavio M, et al. Combined assessment of WT1 and BAALC gene expression at diagnosis may improve leukemia-free survival prediction in patients with myelodysplastic syndromes. Leuk Res. 2015;39(8):866–73. doi: 10.1016/j.leuk.res.2015.04.011.

  45. Hinai A, Valk P. Review: Aberrant EVI1 expression in acute myeloid leukaemia. Br J Haematol. 2016;172(6):870–8. doi: 10.1111/bjh.13898.

  46. Varn FS, Andrews EH, Cheng C. Systematic analysis of hematopoietic gene expression profiles for prognostic prediction in acute myeloid leukemia. Sci Rep. 2015;5(1):16987. doi: 10.1038/srep16987.

  47. Miglino M, Colombo N, Pica G, et al. WT1 overexpression at diagnosis may predict favorable outcome in patients with de novo non-M3 acute myeloid leukemia. Leuk Lymphoma. 2011;52(10):1961–9. doi: 10.3109/10428194.2011.585673.

  48. Zhu YM, Wang PP, Huang JY, et al. Gene mutational pattern and expression level in 560 acute myeloid leukemia patients and their clinical relevance. J Transl Med. 2017;15(1):178. doi: 10.1186/s12967-017-1279-4.

  49. DiNardo CD, Cortes JE. Mutations in AML: prognostic and therapeutic implications. Hematology Am Soc Hematol Educ Program. 2016;2016(1):348–55. doi: 10.1182/asheducation-2016.1.348.

  50. Eisfeld AK, Marcucci G, Maharry K, et al. miR-3151 interplays with its host gene BAALC and independently affects outcome of patients with cytogenetically normal acute myeloid leukemia. Blood. 2012;120(2):249–58. doi: 10.1182/blood-2012-02-408492.

  51. Franzoni A, Passon N, Fabbro D, et al. Histone post-translational modifications associated to BAALC expression in leukemic cells. Biochem Biophys Res 2012;417(2):721–5. doi: 10.1016/j.bbrc.2011.12.013.