Prospects of the development of the mutation status in children with acute lymphoblastic leukemia

October 9, 2018

Objectives — to determine the potential of stratification of children with acute lymphoblastic leukemia (ALL) into prognostic groups using molecular genetic diagnostic techniques apart or in combination with other stratification methods. Materials and methods. The analysis of the chosen literature of years 2010–2018 concerning the problems of prognostication of the effectiveness of treatment in children with ALL at initial diagnosis and after relapse has been performed. Results. To use National Cancer Institute classification for stratifying children into prognostic groups is the most simple and effective method. However, according to the development of molecular genetic methods to analyze the mutational status of genes, and according toverity of publications dedicated to new strategies to use mutational status parameters for detailed stratification of children with ALL, the combined approach may improve the accuracy of prognosis of treatment. Currently, the most studied and significant mutations affecting the prognosis of children with ALL are IKZF1, CDKN2A/B, NRAS/ KRAS, TP53 and PAX5 mutations. Moreover, by identifying the characteristics of the ABL1 gene mutations in patients with translocation t(9;22)/BCR-ABL1, it is possible to achieve better treatment of ALL with protein kinase inhibitors by assigning the most effective generation of the drug. The presence of certain mutations can induce tolerance to certain components of standard scheme of treatment. Thus, NR3C1/BTG1 and CREBBP mutations may be associated with resistance to glucocorticoid therapy and NT5C2 — to nucleoside analogues in children with ALL. After the relapse of ALL, the mutational status of the blast cells is different from its characteristics at the stage of primary diagnosis and should be re-determined. Conclusion. The potentially effective approache for the accurate and comprehensive stratification of children with ALL into prognostic groups is the combine standard scheme and mutational status parameters.

Published: 29.10.2018


  • Barbosa T.C., Terra-Granado E., Quezado Magalhães I.M. et al. (2015) Frequency of copy number abnormalities in common genes associated with B-cell precursor acute lymphoblastic leukemia cytogenetic subtypes in Brazilian children. Cancer Genet., 208(10): 492–501.
  • Boer J.M., Steeghs E.M., Marchante J.R. et al. (2017) Tyrosine kinase fusion genes in pediatric BCR-ABL1-like acute lymphoblastic leukemia. Oncotarget., 8(3): 4618–4628.
  • Brown P.A., Shah B., Fathi A. et al. (2017) NCCN Guidelines Insights: Acute Lymphoblastic Leukemia, Version 1.2017. J. Natl. Compr. Canc. Netw., 15(9): 1091–1102.
  • Clappier E., Grardel N., Bakkus M. et al.; European Organisation for Research and Treatment of Cancer, Children’s Leukemia Group (EORTC-CLG) (2015) IKZF1 deletion is an independent prognostic marker in childhood B-cell precursor acute lymphoblastic leukemia, and distinguishes patients benefiting from pulses during maintenance therapy: results of the EORTC Children’s Leukemia Group study 58951. Leukemia, 29(11): 2154–2161.
  • Dafflon C., Craig V.J., Méreau H. et al. (2017) Complementary activities of DOT1L and Menin inhibitors in MLL-rearranged leukemia. Leukemia, 31(6): 1269–1277.
  • Fang Q., Yuan T., Li Y. et al. (2018) Prognostic significance of copy number alterations detected by multi-link probe amplification of multiple genes in adult acute lymphoblastic leukemia. Oncol. Lett., 15(4): 5359–5367.
  • Gupta S.K., Bakhshi S., Kumar L. et al. (2017) Gene copy number alteration profile and its clinical correlation in B-cell acute lymphoblastic leukemia. Leuk. Lymphoma, 58(2): 333–342.
  • Heerema N.A., Raimondi S.C. (2018) Cytogenetics of Acute Leukemia. In: P. Wiernik, J. Dutcher, M. Gertz (Eds.). Neoplastic Diseases of the Blood. Springer, Cham.
  • Hunger S.P., Mullighan C.G. (2015) Acute Lymphoblastic Leukemia in Children. N. Engl. J. Med., 373(16): 1541–1552.
  • Irving J.A., Enshaei A., Parker C.A. et al. (2016) Integration of genetic and clinical risk factors improves prognostication in relapsed childhood B-cell precursor acute lymphoblastic leukemia. Blood, 128(7): 911–922.
  • Kathiravan M., Singh M., Bhatia P. et al. (2018) Deletion of CDKN2A/B is associated with inferior relapse free survival in pediatric B cell acute lymphoblastic leukemia. Leuk. Lymphoma, Jul. 3 [Epub. ahead of print].
  • Ma X., Edmonson M., Yergeau D. et al. (2015) Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia. Nat. Commun., 6: 6604.
  • Moorman A.V. (2016) New and emerging prognostic and predictive genetic biomarkers in B-cell precursor acute lymphoblastic leukemia. Haematologica, 101(4): 407–416.
  • Moorman A.V., Enshaei A., Schwab C. et al. (2014) A novel integrated cytogenetic and genomic classification refines risk stratification in pediatric acute lymphoblastic leukemia. Blood, 124(9): 1434–1444.
  • Pan L., Liu G., Lin F. et al. (2017) Machine learning applications for prediction of relapse in childhood acute lymphoblastic leukemia. Sci. Rep., 7(1): 7402.
  • Sutton R., Venn N.C., Law T. et al. (2018) A risk score includeing microdeletions improves relapse prediction for standard and medium risk precursor B-cell acute lymphoblastic leukaemia in children. Br. J. Haematol., 180(4): 550–562.
  • Vora A., Goulden N., Mitchell C. et al. (2014) Augmented post-remission therapy for a minimal residual disease-defined high-risk subgroup of children and young people with clinical standard-risk and intermediate-risk acute lymphoblastic leukaemia (UKALL 2003): a randomised controlled trial. Lancet Oncol., 15(8): 809–818.
  • Vrooman L.M., Silverman L.B. (2016) Treatment of Childhood Acute Lymphoblastic Leukemia: Prognostic Factors and Clinical Advances. Curr. Hematol. Malig. Rep., 11(5): 385–394.
  • Wang J., Mi J.Q., Debernardi A. et al. (2015) A six gene expression signature defines aggressive subtypes and predicts outcome in childhood and adult acute lymphoblastic leukemia. Oncotarget., 6(18): 16527–16542.
  • Yohe S. (2015) Molecular Genetic Markers in Acute Myeloid Leukemia. J. Clin. Med., 4(3): 460–478.