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. 2021 Jan 20;22(3):988.
doi: 10.3390/ijms22030988.

Role of HMOX1 Promoter Genetic Variants in Chemoresistance and Chemotherapy Induced Neutropenia in Children with Acute Lymphoblastic Leukemia

Karolina Bukowska-Strakova  1 , Joanna Włodek  1 , Ewelina Pitera  1 , Magdalena Kozakowska  2 , Anna Konturek-Cieśla  2 , Maciej Cieśla  2 , Monika Gońka  2 , Witold Nowak  2 , Aleksandra Wieczorek  3 , Katarzyna Pawińska-Wąsikowska  3 , Alicja Józkowicz  2 , Maciej Siedlar  1
Affiliations

Role of HMOX1 Promoter Genetic Variants in Chemoresistance and Chemotherapy Induced Neutropenia in Children with Acute Lymphoblastic Leukemia

Karolina Bukowska-Strakova et al. Int J Mol Sci. .

Abstract

Whilst the survival rates of childhood acute lymphoblastic leukemia (ALL) have increased remarkably over the last decades, the therapy resistance and toxicity are still the major causes of treatment failure. It was shown that overexpression of heme oxygenase-1 (HO-1) promotes proliferation and chemoresistance of cancer cells. In humans, the HO-1 gene (HMOX1) expression is modulated by two polymorphisms in the promoter region: (GT)n-length polymorphism and single-nucleotide polymorphism (SNP) A(-413)T, with short GT repeat sequences and 413-A variants linked to an increased HO-1 inducibility. We found that the short alleles are significantly more frequent in ALL patients in comparison to the control group, and that their presence may be associated with a higher risk of treatment failure, reflecting the role of HO-1 in chemoresistance. We also observed that the presence of short alleles may predispose to develop chemotherapy-induced neutropenia. In case of SNP, the 413-T variant co-segregated with short or long alleles, while 413-A almost selectively co-segregated with long alleles, hence it is not possible to determine if SNPs are actually of phenotypic significance. Our results suggest that HO-1 can be a potential target to overcome the treatment failure in ALL patients.

Keywords: chemotherapy induced neutropenia; heme oxygenase-1; minimal residual disease; pediatric acute lymphoblastic leukemia.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Relapse-free survival by grouping patients according to the presence of (A) length polymorphism and (B) SNPs polymorphisms. (A) The 5-year actuarial probability of relapse-free survival was 62.5%, 80.7% and 95.5% for patients with SS (red line, n = 8), SL (gray line, n = 26) and LL (black line, n = 22) genotype, respectively. (B) The 5-year actuarial probability of relapse-free survival was 88.2%, 86.7% and 75% for patients with TT (red line, n = 12) genotype, AT (gray line, n = 30) and AA (black line, n = 17), respectively.
Figure 2
Figure 2
Co-segregation of the A and T alleles with HMOX1 promoter length variants: (A) Shown as a percentage frequency distribution of AA, AT and TT genotype in SS, SL and LL individuals (both patients and control group); (B) distribution of AA and TT in individuals with certain length variants, separately in the patient and control group; S—short alleles (GT n < 24), M—medium alleles (24–28 GT n), L—long alleles (29/30 GT n), L—very long alleles (GT n > 30).
Figure 3
Figure 3
(A) Frequencies of short and long alleles in the patient and control groups. In ALL patients: 43 short alleles (38.4%) and 69 long alleles (61.6%); in control group: 20 short alleles (23.8%) and 64 long alleles (76.2%). (B) Comparison of percentage of patients and healthy controls with the SS, SL or LL genotype. In ALL patients: SS genotype—8 patients (14.3%), SL genotype—27 patients (48.2%), LL genotype—21 patients (37.5%). In controls group: SS genotype—4 individuals (9.5%), SL genotype—12 individuals (28.6%), LL genotype—26 individuals (61.9%). *—p < 0.05.
Figure 4
Figure 4
(A) Frequencies of short and long alleles in the control group and in patients stratified into the risk groups. In the control group: 20 short alleles (23.8%) and 64 long alleles (76.2%); in the SR group: 9 short alleles (28.1%) and 23 long alleles (71.9%); in the IR group: 22 short alleles (36.7%) and 38 long alleles (63.3%); in the HR group: 12 short alleles (60%) and 8 long alleles (40%); (B) Comparison of percentage of individuals with the SS, SL and LL genotypes in the control group and in patients stratified into the particular risk groups. In the control group: SS genotype—4 individuals (9.5%), SL genotype—12 individuals (28.6%), LL genotype—26 individuals (61.9%). In the SR group: SS genotype—0 patients, SL genotype—9 patients (56.2%), LL genotype—7 patients (43.8%). In the IR group: SS genotype—4 patients (13.3%), SL genotype—14 patients (46.7%), LL genotype—12 patients (40%). In the HR group: SS genotype—4 patients (40%), SL genotype—4 patients (40%), LL genotype—2 patients (20%). *—p < 0.05; **—p < 0.01.
Figure 5
Figure 5
(A) MRD level at 33rd day of treatment in association with the presence of short alleles in patients, shown in all patients and separately in patients stratified into the particular risk groups. Mean MRD was 0.086 ± 0.17 in patients with at least one S allele versus mean MRD 0.0033 ± 0.006 in the LL patients. In the SR group—data available for 15 patients, in the IR group for 28 patients, in the HR group for 10 patients. (B) CIN incidences in association with the presence of short alleles in patients, shown in all patients, and separately in patients stratified into the particular risk groups. Then the influence of genotype and a risk group was calculated as independent variables on a number of CIN incidents. It appeared that the main effect resulted from the risk group (two-way ANOVA, p = 0.0005), but there was also an effect of genotype (p = 0.0055). In the SR group—data available for 15 patients, in the IR group for 24 patients, in the HR group for 10 patients. Data are presented as means and SEM * p < 0.05, ** p < 0.01.
Figure 6
Figure 6
Confocal microscopy slides displaying HO-1 protein (green) and nuclear staining (blue) in normal bone marrow hematopoietic stem and myeloid progenitor cells, as well as B-cell developmental stages. HSC—hematopoietic stem cells, MPP—multipotent progenitors, CMP—common myeloid progenitors, GMP—granulocyte-macrophage progenitor, MEP—megakaryocyte-erythroid progenitor, CLP—common lymphoid progenitor.
Figure 7
Figure 7
(A) Comparison of HMOX1 mRNA level in peripheral blood samples taken from healthy, untreated children (n = 3) and from ALL children (n = 19) during treatment course, at stage of clinical remission when no blast cells were found in the blood, and complete blood count was normalized. (B) Basal HO-1 expression (shown as MFI) in leukemic cells and the residual normal cell subsets present in the sample at the day of diagnosis (n = 11). (C) MFI of HO-1 in each cell subset before treatment (n = 11) and at day 15th (n = 6) and 33rd (n = 3) of induction. (D) The fold increase of HO-1 expression in monocytes in relation to the risk group and to treatment response, expressed as MRD level. Blasts—leukemic cells, lymph B—mature lymphocytes, EBL—erythroblasts, mono—monocytes. *—p< 0.05; **—p < 0.01; ***—p < 0.001.
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