Impact of BCOR/BCORL1 mutation on outcomes of allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia patients
- Open Access
- 09.04.2025
- Review
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Abstract
Introduction
The gene BCOR, a transcription factor, located on chromosome X at p11.4, is involved in lymphocyte development, function of hematopoietic and mesenchymal stem cells, and pluripotency of embryonic stem cells [1]. It was first identified in a 2-hybrid screen for interactors with transcriptional repressor BCL6, whose alteration can lead to diffuse large B cell lymphomas [2]. Genetic lesions of BCOR have also been shown to be associated with hematopoietic malignancies [3]. Researchers have detected BCOR mutations were detected in 3.8–5.0% of adult de novo acute myeloid leukemia (AML) and 8% of secondary AML [4‐6], previous studies have confirmed that BCOR mutations are associated with adverse prognosis in AML. As a result, they were classified into the adverse-risk group as per the 2022 European Leukemia Net (ELN) recommendations [4, 7‐11]. Furthermore, BCOR mutations have also been found to be involved in the proliferation and differentiation of hematopoietic cells and to play an important role in transcriptional and epigenetic regulation [4, 12]. They also cause disorderly proliferation of myeloid progenitor cells and inhibit differentiation [1, 12, 13].
BCORL1, located at chromosome Xq26.1, is a homologous gene of BCOR. The prevalence of BCORL1 mutations is similar to BCOR-mutated AML, at 3.7–5.8% in AML adult patients [5, 14], but despite their many similarities, the BCOR and BCORL1 genes exhibit some different features in terms of the capability to interact with BCL6, localization within subnuclear structures, and expression levels in human tissues [6].
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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only potentially curative treatment for many high-risk AML patients [11, 15, 16]. However, although the impact of BCOR and/or BCORL1 mutations (BCOR/BCORL1mut) on AML patients are well-established in chemotherapy cohorts, the clinical significance of BCOR/BCORL1mut is less clear in transplant patients. We therefore performed a retrospective analysis in an attempt to determine the clinical characteristics and transplant outcomes of BCOR- and BCORL1-mutated AML.
Subjects and methods
Subjects enrollment and definitions
We retrospectively investigated a cohort of 877 consecutive adult AML subjects, who received their first allo-HSCT from January, 2018 to December, 2023, based on the National Longitudinal Cohort of Hematological Diseases (NICHE, NCT04645199) from the Institute of Hematology and Blood Diseases Hospital, Peking Union Medical College, and the Chinese Academy of Medical Sciences (IHCAMS). Eventually, 83 (9.5%) subjects with BCOR/BCORL1mut at diagnosis were identified. Additionally, we also enrolled 276 AML patients with normal karyotypes, defined as the BCOR/BCORL1wt group (Fig. 1a).
Fig. 1
Subjects enrollment, and characteristic of BCOR and BCORL1 mutation. (a) Criteria for inclusion and exclusion of subjects. (b) Lollipop plot showing various mutations across the BCOR and BCORL1 mutations. (c) Co-mutational profile in BCOR/BCORL1-mutated and normal karyotype AML. (d) 2022 ELN risk stratification and variant allele frequency (VAF) in BCOR/BCORL1-mutated patients
The following criteria were utilized to diagnose and evaluate patient disease status. The diagnosis of AML adhered to the 2016 World Health Organization (WHO) guidelines and disease risk was assessed using the 2022 ELN [11, 17]. Minimal residual disease negativity (MRD) was assessed using multiparameter flow cytometry, and MRD positivity was defined as levels > 0.01%. The definition of complete remission (CR) included bone marrow (BM) blasts of less than 5%, the absence of circulating blasts, and no extramedullary disease [11]. Relapse was defined as the presence of 5% or more leukemic blasts in the BM, the reappearance of leukemic blasts in peripheral blood (PB) in at least two PB samples taken at least one week apart, or the emergence of new extramedullary disease [11]. Patients were classified as having refractory disease if a specified response was not achieved by a designated landmark (such as failure to attain a response after two cycles of intensive chemotherapy) or a predetermined landmark (for example, 180 days after initiating less-intensive therapy) [11].
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This study was approved by the Ethics Committee at IHCAMS and adhered to the Declaration of Helsinki. All patients provided written informed consent to participate.
Targeted gene sequencing
The protocol for carrying out targeted gene sequencing has been described previously [18]. In brief, genomic DNA was extracted from BM specimens, targeting at least 141 genes involved in point mutations and insertion/deletion mutations in protein-coding regions or hotspots (Table S1). Exons of these genes were sequenced with a depth of 800×, ion and variant reporters were used for mutation analysis. Databases such as dbSNP, 1000 Genomes, Polyphen-2, and COSMIC were used for mutation annotation and amino acid mutation analysis. Using this method, the detection rate of mutation sites with 5% mutation frequency was more than 97%.
Transplantation procedure
All patients included in this study received intensive induction chemotherapy prior to allo-HSCT. The standard anthracycline and cytarabine-based regimen was used for induction chemotherapy, followed by consolidation chemotherapy, which typically involves primary induction chemotherapy or high-dose cytarabine. All patients received a modified myeloablative conditioning (MAC) regimens based on busulfan (Bu) and cyclophosphamide (Cy). For mismatched related donors and unrelated donors (URD), anti-thymocyte globulin (ATG, 2-2.5 mg/kg/day on days − 4 to -1) was required, and donor peripheral blood stem cells were collected following G-CSF mobilization (5–10 µg·kg− 1·day− 1 for 5–6 days). Cyclosporine (CAS) or Tacrolimus (FK506) in combination with a short course of methotrexate (MTX) with or without mycophenolate mofetil (MMF) were used for the prophylaxis of acute graft versus host donor (GVHD). Acute GVHD was graded according to MAGIC criteria and severity of chronic GVHD was determined using the 2014 National Institute of Health consensus criteria [19, 20]. Methylprednisolone was used as the first-line treatment for acute GVHD. Neutrophil engraftment was defined as the first neutrophil count more than 0.5 × 109 /L for 3 consecutive days and platelet engraftment was defined as the first platelet count more than 20 × 109 /L without transfusion for 7 consecutive days. The post-transplant disease status of BM was assessed at days + 14, +28, + 42 and months + 2, +3, + 4.5, + 6, +9 and + 12.
Statistical analysis
The statistical comparison of categorical variables was performed using chi-squared tests or Fisher’s exact tests and continuous variables were compared using t tests or Kruskal-Wallis tests. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method and log-rank test. Cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were estimated using competing risk model analysis and Fine-Grey’s test. OS and DFS were defined as the time from transplantation to death and relapse or death, respectively; CIR was defined as the time from transplantation to relapse and with non-relapse mortality (NRM) as the time from transplantation to death without relapse. Univariate and multivariate analysis were both used to assess the association between survival outcomes and clinical characteristics of the patients. Variables with P values < 0.1 in univariate analysis were included in the multivariate Cox models and competing risk models. A P value < 0.05 was considered to indicate statistical significance in each of these multivariate models. Statistical analysis was performed using R 4.3.3 and SPSS 26.
Results
The BCOR/BCORL1mut landscape
Out of the 877 consecutive NGS tests performed, 83 (9.5%) subjects with BCOR/BCORL1mut were identified. BCOR and BCORL1 alterations occurred in 56 (6.4%) and 38 (4.3%) patients, respectively, with 11 (13.3%) instances of BCOR and BCORL1 co-mutation. BCOR mutations were frequent in exon 4 (43%), and BCORL1 mutations were frequent in exon 3 (77%) (Fig. 1c, d). Frameshift mutation was the predominant alteration of BCOR (n = 22, 39.3%), followed by missense variants (n = 18, 32.1%), and missense mutation account for the majority of BCORL1 mutations (n = 25, 65.8%). The plurality of alterations occurred outside the functional domains (n = 74, 89.2%). Alteration of AF9BD domain of BCOR, which directly interacts with the transcriptional regulator AF9 (MLLT3) [2, 21, 22], was present in 12.5% (n = 7) patients, and the ANK domain of BCORL1 was altered in 2 (5.3%) patients (Fig. 1b). The average variant allele frequency (VAF) of BCOR and BCORL1 genes were 42.7% (range 1.7-100.0%) and 48.1% (range 2.5-100.0%), respectively.
The median co-occurring mutations of BCOR/BCORL1mut was 4 (range 0–10), and the most common co-mutated gene was DNMT3A (n = 23, 27.7%), followed by genes NRAS (n = 21, 25.3%), FLT3 (n = 21, 25.3%), RUNX1 (n = 20, 24.1%), and WT1 (n = 14, 16.9%), but only 4 (4.8%) patients co-occured TP53 mutations. For FLT3-mutated patients, 13 had FLT3-ITD mutations and 8 had FLT3-TKD mutations, respectively. In BCOR/BCORL1wt patients, FLT3 (n = 114, 41.3%), NPM1 (n = 86, 31.2%), DNMT3A (n = 69, 25.0%), and CEBPA (n = 61, 22.1%) mutations were more frequent (Fig. 1c).
According to ELN 2022, 9 (10.8%) patients were classified as favorable-risk, including 3 with t(8;21), 3 with NPM1 mutation without FLT3-ITD mutation, and 3 with bZIP in-frame mutated CEBPA, 19 (22.9%) were intermediate-risk, and 55 (66.3%) were adverse-risk. Notably, the intermediate-risk patients had higher VAF compared to the adverse-risk patients (Median: 67.6 vs. 42.7, P < 0.01) (Fig. 1d). In terms of cytogenetic abnormality, 86.75% (n = 72) of BCOR/BCORL1mut patients had normal karyotypes.
Characteristics of BCOR/BCORL1mut
A total of 359 AML patients who received their first allo-HSCT were included in this study. The median age was 38 [interquartile range (IQR), 30–48] years. Of the 359 patients, 83 (23.1%) cases had BCOR/BCORL1mut and 276 (76.9%) patients with normal karyotypes were enrolled in the BCOR/BCORL1wt group. The clinical characteristics of the BCOR/BCORL1mut and BCOR/BCORL1wt groups are summarized in Table 1. The median age of the BCOR/BCORL1mut group was 38 (IQR, 33–48) years, similar to that of the BCOR/BCORL1wt group (38 [IQR, 29–49] years, P = 0.26). The median WBC counts at initial diagnosis of BCOR/BCORL1mut was significantly lower than that in BCOR/BCORL1wt group (6.79 [IQR, 2.41–29.96] vs. 20.53 [IQR, 3.54–60.80] ×109/L, P = 0.003). Patients with BCOR/BCORL1mut were more frequently categorized within the 2022 ELN adverse-risk group (66.3% vs. 25.7%, P < 0.001), and fewer achieved pre-transplant MRD negativity (61.5% vs. 79.7%, P < 0.001). In the BCOR/BCORL1mut group, the time interval from diagnosis to transplantation was significantly shorter than BCOR/BCORL1wt group as well (6.6 [IQR, 5.6–8.1] months vs. 7.2 [IQR, 5.8–10.0] months, P = 0.04). Additionally, the HCT-CI scores of BCOR/BCORL1mut patients were significantly higher than that of BCOR/BCORL1wt patients (P < 0.001). Other baseline characteristics between the two groups were similar, including donor type, GVHD prophylaxis, and gender matching.
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Table 1
Patient characteristics of BCOR/BCORL1mut and BCOR/BCORL1wt group
Characteristics | Total | BCOR/BCORL1mut | BCOR/BCORL1wt | P |
|---|---|---|---|---|
(n = 359) | (n = 83) | (n = 276) | ||
Age (years), Mean (Q₁, Q₃) | 38 (30, 48) | 38 (33, 48) | 38 (29, 49) | 0.256 |
Sex, n (%) | 0.984 | |||
Female | 177 (49.30) | 41 (49.40) | 136 (49.28) | |
Male | 182 (50.70) | 42 (50.60) | 140 (50.72) | |
WBC (×109/L), Mean (Q₁, Q₃) | 17.33 (2.99, 51.30) | 6.79 (2.41, 29.96) | 20.53 (3.54, 60.80) | 0.003 |
BM blasts, Mean (Q₁, Q₃) | 54.0 (26.0, 77.6) | 44.0 (31.0, 72.0) | 56.00(24.5, 78.5) | 0.629 |
ELN 2022 risk group, n (%) | < 0.001 | |||
Favorable | 84 (23.40) | 9 (10.84) | 75 (27.17) | |
Intermediate | 149 (41.50) | 19 (22.89) | 130 (47.10) | |
Adverse | 126 (35.10) | 55 (66.27) | 71 (25.72) | |
r/r AML, n (%) | 0.152 | |||
No | 260 (72.42) | 55 (66.27) | 205 (74.28) | |
Yes | 99 (27.58) | 28 (33.73) | 71 (25.72) | |
Time from diagnosis to transplantation (months), Mean (Q₁, Q₃) | 7.1 (5.8, 9.2) | 6.6 (5.6, 8.1) | 7.2 (5.8, 10.0) | 0.037 |
Pre-transplant status, n (%) | < 0.001 | |||
CR-MRD (-) | 271 (75.49) | 51 (61.45) | 220 (79.71) | |
CR-MRD (+) | 39 (10.86) | 18 (21.69) | 21 (7.61) | |
NOT-CR | 49 (13.65) | 14 (16.87) | 35 (12.68) | |
HCT-CI score, n (%) | < 0.001 | |||
≤ 1 | 317 (88.30) | 60 (72.29) | 257 (93.12) | |
> 1 | 42 (11.70) | 23 (27.71) | 19 (6.88) | |
HSCT type, n (%) | 0.403 | |||
HID | 227 (63.23) | 49 (59.04) | 178 (64.49) | |
MSD | 115 (32.03) | 28 (33.73) | 87 (31.52) | |
URD | 17 (4.74) | 6 (7.23) | 11 (3.99) | |
Prophylaxis of acute GVHD, n (%) | 0.7 | |||
CSA + MTX ± MMF | 184 (51.25) | 41 (49.40) | 143 (51.81) | |
FK506 + MTX ± MMF | 175 (48.75) | 42 (50.60) | 133 (48.19) | |
Gender match, n (%) | 0.886 | |||
Female to Female | 61 (16.99) | 13 (15.66) | 48 (17.39) | |
Female to Male | 62 (17.27) | 15 (18.07) | 47 (17.03) | |
Male to Female | 119 (33.15) | 30 (36.14) | 89 (32.25) | |
Male to Male | 117 (32.59) | 25 (30.12) | 92 (33.33) |
Survival and relapse
The median follow-up time of the 359 patients was 35.4 (95% CI, 32.3–38.5) months. Three-year OS, DFS, and CIR were 75.5% (95% CI, 70.8-80.4%), 73.3% (95% CI, 68.6-78.3%) and 14.9% (95% CI, 11.2-19.1%), respectively. The median follow-up time for the BCOR/BCORL1mut and BCOR/BCORL1wt groups were 34.8 (95% CI, 25.0-44.6) and 36.0 (95% CI, 32.1–39.9) months, and the maximum follow-up times were 77.0 and 73.3 months, respectively. By the end of follow-up, 17 (20.5%) patients in the BCOR/BCORL1mut group had died, of whom 11 (64.7%) died from relapse, 2 (11.8%) died from grade IV acute GVHD, 3 (17.6%) died from pulmonary infection, and 1(5.9%) died from unknown cause.
The median survival time of the BCOR/BCORL1mut group was 73.4 (95% CI, 33.8–113.0) months, but that of the BCOR/BCORL1wt group was not reached. Furthermore, the three-year OS of the BCOR/BCORL1mut and BCOR/BCORL1wt groups was 76.0% (95% CI, 66.0-87.5%) vs. 75.2% (95% CI, 70.0-80.8%) (HR, 0.92; 95% CI, 0.54–1.57; P = 0.77), respectively (Fig. 2a); the three-year DFS of the BCOR/BCORL1mut and BCOR/BCORL1wt groups was 67.7% (95% CI, 57.0-80.4%) vs. 74.5% (95% CI, 69.4-80.1%) (HR, 1.20; 95% CI, 0.75–1.91; P = 0.46), respectively (Fig. 2b); the three-year CIR of the BCOR/BCORL1mut and BCOR/BCORL1wt groups was 24.0% (95% CI, 14.1-35.4%) vs. 12.6% (95% CI, 8.9-17.0%) (HR, 1.85; 95% CI, 1.04–3.3; P = 0.03), respectively (Fig. 2c); and the three-year NRM of the BCOR/BCORL1mut and BCOR/BCORL1wt groups was 8.3% (95% CI, 3.3-16.2%) vs. 12.9% (95% CI, 9.1-17.2%) (HR, 0.58; 95% CI, 0.25–1.38; P = 0.22), respectively (Fig. 2d).
Fig. 2
Transplant outcomes of acute myeloid leukemia patients with BCOR/BCORL1mut and BCOR/BCORL1wt. (a) Overall survival. (b) Disease-free survival. (c) Cumulative incidence of relapse. (d) Cumulative incidence of non-relapse mortality
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Clinical outcomes of the four groups, including BCORwt/BCORL1wt, BCORmut/BCORL1wt, BCORwt/BCORL1mut, and BCORmut/BCORL1mut patients, were also analyzed. No significant differences were observed in OS, DFS, CIR, or NRM among any of these groups. However, the CIR was significantly higher in BCORmut/BCORL1wt patients compared to BCORwt/BCORL1wt patients (3-year CIR: 29.0% [95% CI, 15.0-44.7%] vs. 12.6% [95% CI, 8.9-17.0%], HR, 2.44 [95% CI, 1.28–4.65], P = 0.007), but no significant difference was found between BCORmut/BCORL1wt and BCORwt/BCORL1mut group (3-year CIR: 29.0% [95% CI, 15.0-44.7%] vs. 20.0% [95% CI, 5.8%-4.3%], HR, 0.53 [95% CI, 0.18–1.59], P = 0.26) (Fig S1).
We also compared the prognostic differences between BCOR/BCORL1mut and BCOR/BCORL1wt groups across different MRD statuses, 2022 ELN risk stratifications, and donor types. Notably, we observed that BCOR/BCORL1mut in patients undergoing matched sibling donor (MSD) transplantation were associated with an increased relapse rate (HR, 3.48; 95% CI, 1.41–8.60; P = 0.01) but lower NRM (HR, 0; 95% CI, 0-Inf; P = 0.02) after allo-HSCT. No difference between other conditions was found (Table S2).
Risk factors analysis
As shown by the results above, we further conducted univariate and multivariate analyses in 359 patients to assess whether BCOR/BCORL1mut was an independent risk factor for CIR after transplantation (Table 2). These results showed that BCOR/BCORL1mut was associated with increased CIR after allo-HSCT in univariate analysis (HR, 1.85; 95% CI, 1.04–3.3; P = 0.03) but was not an independent risk factor in multivariate analysis (HR, 1.31; 95% CI, 0.59–2.87; P = 0.51). Additionally, pre-transplant MRD positivity (HR, 2.56; 95%CI, 1.01–6.46; P = 0.04) and not-CR (HR, 5.63; 95% CI, 2.69–11.82; P < 0.001) independently predicted an unfavorable outcome for CIR. Univariate and multivariate analysis for OS and DFS were also conducted and detailed results are listed in Table 2.
Table 2
Univariate and multivariate analysis in 359 AML patients
OS | Univariate analysis | Multivariate analysis |
|---|---|---|
HR (95% CI) p-value | HR (95% CI) p-value | |
Age (years) | ||
≥ 50 vs. < 50 | 1.64 (1.03–2.60) 0.04 | 1.65 (1.03–2.66) 0.04 |
Sex | ||
Female vs. male | 1.25 (0.82–1.93) 0.30 | |
WBC (×109/L) | ||
≥ 100 vs. < 100 | 0.97 (0.50–1.87) 0.92 | |
Bone marrow blasts | ||
≥ 50% vs. < 50% | 0.78 (0.51–1.20) 0.26 | |
BCOR/BCORL1 mutation | ||
Yes vs. no | 0.92 (0.54–1.57) 0.77 | |
2022 ELN | ||
Intermediate vs. favorable | 2.36 (1.21–4.62) 0.01 | 2.32 (1.18–4.56) 0.01 |
Adverse vs. favorable | 2.61 (1.32–5.16) 0.01 | 1.82 (0.89–3.70) 0.10 |
Pre-HSCT status | ||
CR-MRD (+) vs. CR-MRD (-) | 1.90 (1.03–3.54) 0.04 | 1.68 (0.88–3.20) 0.11 |
NOT-CR vs. CR-MRD (-) | 3.28 (2.00–5.35) < 0.001 | 3.06 (1.82–5.15) < 0.001 |
HCT-CI score | ||
> 1 vs. ≤ 1 | 1.56 (0.86–2.82) 0.14 | |
Donor type | ||
HID vs. MSD | 0.96 (0.61–1.51) 0.86 | |
URD vs. MSD | 0.45 (0.11–1.87) 0.27 | |
Acute GVHD prophylaxis | ||
FK506 + MTX ± MMF vs. CSA + MTX ± MMF | 1.05 (0.69–1.61) 0.81 | |
DFS | ||
Age (years) | ||
≥ 50 vs. < 50 | 1.58 (1.01–2.46) 0.04 | 1.52 (0.97–2.39) 0.07 |
Sex | ||
Female vs. male | 1.36 (0.90–2.04) 0.14 | |
WBC (×109/L) | ||
≥ 100 vs. < 100 | 0.83 (0.43–1.61) 0.59 | |
Bone marrow blasts | ||
≥ 50% vs. < 50% | 0.74 (0.49–1.11) 0.14 | |
BCOR/BCORL1 mutation | ||
Yes vs. no | 1.19 (0.75–1.91) 0.46 | |
2022 ELN | ||
Intermediate vs. favorable | 1.97 (1.05–3.70) 0.03 | 1.94 (1.03–3.65) 0.04 |
Adverse vs. favorable | 2.78 (1.49–5.19) 0.001 | 1.99 (1.04–3.82) 0.04 |
Pre-HSCT status | ||
CR-MRD (+) vs. CR-MRD (-) | 1.96 (1.09–3.53) 0.03 | 1.66 (0.90–3.06) 0.10 |
NOT-CR vs. CR-MRD (-) | 3.28 (2.05–5.24) < 0.001 | 2.88 (1.75–4.72) < 0.001 |
HCT-CI score | ||
> 1 vs. ≤ 1 | 1.33 (0.74–2.38) 0.34 | |
Donor type | ||
HID vs. MSD | 0.85 (0.56–1.30) 0.45 | |
URD vs. MSD | 0.36 (0.09–1.52) 0.17 | |
Acute GVHD prophylaxis | ||
FK506 + MTX ± MMF vs. CSA + MTX ± MMF | 1.10 (0.73–1.65) 0.65 | |
CIR | ||
Age (years) | ||
≥ 50 vs. < 50 | 1.00 (0.56–2.01) 0.87 | |
Sex | ||
Female vs. male | 1.41 (0.82–2.43) 0.22 | |
WBC (×10*9/L) | ||
≥ 100 vs. < 100 | 0.74 (0.30–1.86) 0.52 | |
Bone marrow blasts | ||
≥ 50% vs. < 50% | 0.48 (0.27–0.85) 0.01 | 0.86 (0.35–2.08) 0.73 |
BCOR/BCORL1 mutation | ||
Yes vs. no | 1.85 (1.04–3.3) 0.03 | 1.31 (0.59–2.87) 0.51 |
2022 ELN | ||
Intermediate vs. favorable | 1.42 (0.59–3.39) 0.43 | 1.44 (0.54–3.82) 0.46 |
Adverse vs. favorable | 3.39 (1.51–7.59) 0.003 | 1.27 (0.49–3.29) 0.63 |
Pre-HSCT status | ||
CR-MRD (+) vs. CR-MRD (-) | 2.30 (1.04–5.08) < 0.001 | 2.56 (1.01–6.46) 0.04 |
NOT-CR vs. CR-MRD (-) | 4.48 (2.42–8.28) < 0.001 | 5.63 (2.69–11.82) < 0.001 |
HCT-CI score | ||
> 1 vs. ≤ 1 | 1.02 (0.43–2.43) 0.96 | |
Donor type | ||
HID vs. MSD | 0.90 (0.52–1.58) 0.72 | |
URD vs. MSD | 0.35 (0.05–2.61) 0.30 | |
Acute GVHD prophylaxis | ||
FK506 + MTX ± MMF vs. CSA + MTX ± MMF | 0.87 (0.51–1.49) 0.61 |
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Impact of mutation characteristics on transplant outcomes
We investigated whether the type and location of BCOR/BCORL1mut influenced transplant outcomes. Strikingly, there was no significant difference in DFS or CIR between patients with frameshift or other types of mutation (Fig. 3a, b), and comparable results were also found for the location of mutations (Fig. 3c, d). The three-year OS, DFS, and CIR of patients with frameshift mutations and other types of mutations were 88.1% (95% CI, 76.3-100.0%) vs. 71.1% (95% CI, 58.6-86.2%) (HR, 0.58; 95% CI, 0.19–1.78; P = 0.34), 74.1% (95% CI, 57.2-96.0%) vs. 64.5% (95% CI, 51.6-80.8%) (HR, 0.75; 95% CI, 0.29–1.89; P = 0.53) and 22.2% (95% CI, 6.9-42.8%) vs. 24.9% (95% CI, 12.9-38.9%) (HR, 0.91; 95% CI, 0.32–2.60; P = 0.86), respectively. The three-year OS, DFS, and CIR of patients with C-terminal domains mutations and other locations of mutations were 100.0% (95% CI, 100.0%-100.0%) vs. 74.9% (95% CI, 64.6-86.8%) (HR, 0; 95% CI, 0-InF; P = 0.33), 100.0% (95% CI, 100.0%-100.0%) vs. 66.2% (95% CI, 55.2-79.3%) (HR, 0; 95% CI, 0-InF, P = 0.25), and 0 vs. 25.1% (95% CI, 14.8-36.7%) (HR, 0; 95% CI, 0-InF; P = 0.33), respectively (Table 3).
Fig. 3
Impact of BCOR and BCORL1 mutation characteristics on transplant outcomes. (a) Disease-free survival (DFS) and (b) cumulative incidence of relapse (CIR) in patients with frameshift and other type of mutation. DFS (c) and CIR (d) in patients with alteration in C-terminal domain and other locations
Table 3
Three-year OS, DFS and CIR of patients with different mutation type and location in BCOR/BCORL1mut group
Mutation type | Mutation location | |||
|---|---|---|---|---|
Frame shift | other types | C- terminal domains | other locations | |
OS | ||||
Three-year OS (95%CI) | 88.1% (76.3-100.0%) | 71.1% (58.6-86.2%) | 100.0% (100.0%-100.0%) | 74.9% (64.6-86.8%) |
HR (95%CI) p-value | 0.58 (0.19–1.78) P = 0.34 | 0 (0-InF) P = 0.33 | ||
DFS | ||||
Three-year DFS (95%CI) | 74.1% (57.2-96.0%) | 64.5% (51.6-80.8%) | 100.0% (100.0%-100.0%) | 66.2% (55.2-79.3%) |
HR (95%CI) p-value | 0.75 (0.29–1.89) P = 0.53 | 0 (0-InF) P = 0.25 | ||
CIR | ||||
Three-year CIR (95%CI) | 22.2% (6.9-42.8%) | 24.9% (12.9-38.9%) | 0 | 25.1% (14.8-36.7%) |
HR (95%CI) p-value | 0.91 (0.32–2.60) P = 0.86 | 0 (0-InF) P = 0.33 | ||
Discussion
BCOR and BCORL1 are key transcription factors and function as components of PRC1.1, a noncanonical PRC1 complex, that monoubiquitinates histone 2 A at lysine 119 and mediates transcriptional repression [23]. BCOR mutations have been widely reported in patients with hematologic malignancies and mesenchymal tumors [3]. For AML, BCOR/BCORL1mut ranges from less than 10% and occurs primarily in cytogenetically normal AML (CN-AML) [4]. In the 2022 ELN risk stratification, BCOR mutations are classified as an adverse prognostic marker, suggesting that AML patients with BCOR mutations are more likely to be classified into the adverse-risk group. For these patients, the importance of allo-HSCT is heightened [11]. BCOR/BCORL1mut has also been reported with a reduced DFS, but this did not significantly affect OS in an unselected cohort [4, 7, 8]. However, the role of BCOR/BCORL1mut in allo-HSCT remains unclear. In this study, we described the clinical characteristics and transplant outcomes of eighty-three BCOR/BCORL1mut AML patients and compared them to CN-AML. To our knowledge, this is the largest study to examine the influence of BCOR/BCORL1mut in a transplant cohort.
The prevalence of BCOR and BCORL1 mutations in our patients were 6.4% and 4.3%, respectively, consistent with previous studies [6, 7, 14]. We observed lower WBC counts at diagnosis in BCOR- and BCORL1-mutated patients, and previous studies have also suggested that AML patients with BCOR mutation are characterized by excessive proliferation of blasts and reduced leukocyte hyperplasia [12, 13, 24]. We also observed that BCOR-mutated AML showed a lower CR rate pre-transplantation. Japan researchers have also reported a significantly lower CR rate (47.4% vs. 71.8%, P = 0.0357) in cases with BCOR/BCORL1mut than in cases with BCOR/BCORL1wt [5]. In mechanistic terms, research has demonstrated that BCOR knockout cell lines exhibit reductions in sensitivity to chemotherapy with Idarubicin and Ara-C in mice model [25]. A lower CR rate also contributes to a shorter interval to transplantation in BCOR/BCORL1mut patients.
In the present study, we found that the predominant type of BCOR mutation was frameshift mutations, followed by missense mutation; and missense mutation accounted for the majority of BCORL1 mutations. These results coincide with those reported previously [4, 8, 26]. The therapeutic impact of mutation characteristics has not been totally established. Abuhadra et al. reported a median OS of 10.9 months for patients with frameshift mutations, compared to 50.4 months for patients with other types of mutations (P = 0.03) [26], though we did not find a significant difference in transplant outcomes between cases with frameshift mutations and those with other mutation types. Mutation location has also been reported to be associated with clinical outcomes [26]. At present, four functional domains of the BCOR gene were well-established, including BBD, AF9BD, ANK repeats and PUFD [1], and the BCORL1 gene is characterized by the CBS, 2 LXXLL, ANK repeats, and PUFD [1]. BCOR altered at C-terminal tandem ANK was reported to have a lower OS than mutations at other positions [26]. In this study, the distribution of mutation sites was quite diverse and most mutations were located out of functional domains. Our analysis showed that mutations occurring at the C-terminal domain had no significant effect on transplant outcomes. These results indicate that allo-HSCT may overcome the prognostic impact of mutation type and location.
AML can stem from multiple mutations [10, 11, 27, 28]. BCOR mutations have been reported to be mutually exclusive with NPM1 mutations, and associated with a lower incidence of FLT3-ITD mutations, and to have an association with DNMT3A and RUNX1 mutations [4, 5, 7], which are all consistent with our findings except for the higher frequency of the co-mutation rate of FLT3 gene in our cohort. The fact that our subjects were exclusively Chinese may explain this, however, because of the combined effects of genetic background, disease distribution, and environmental factors. DNMT3A mutation is associated with poor survival outcomes, and co-mutation of BCOR and DNMT3A has been widely reported [29‐31]. Researchers speculated that these two mutations may act synergistically to induce AML by interfering with epigenetic mechanisms, though more research is needed to confirm [32].
Most BCOR-mutated AML patients carry normal karyotypes [4]. Several studies have compared BCOR-mutated AML with CN-AML in chemo-based cohorts and found a shorter OS in BCOR-mutated AML patients. In addition, they have also indicated that allo-HSCT can reverse the adverse outcomes caused by BCOR mutations [33]. However, the impact of BCOR/BCORL1mut on transplant outcomes has yet to be reported specifically. In our present study, the OS, DFS, and NRM of BCOR/BCORL1mut patients were quite similar to outcomes of BCOR/BCORL1wt patients. Notably, BCOR/BCORL1mut patients had a higher CIR after transplantation compared to BCOR/BCORL1wt patients, suggesting a potential impact of BCOR/BCORL1 mutations on relapse. We also observed a slightly higher NRM in the BCOR/BCORL1wt group, which might explain the equivalent DFS between BCOR/BCORL1mut and BCOR/BCORL1wt patients, despite the increased CIR in the BCOR/BCORL1mut group. Although the difference in NRM between the two groups was not statistically significant, the interval from diagnosis to transplantation, the number of chemotherapy cycles, and immune status may all be potential factors that influence NRM. Although further analysis showed that BCOR/BCORL1mut was not an independent risk factor for CIR, it was strongly related to a higher CIR post-transplantation and thus a potentially beneficial future research direction would be to perform a large registry study to observe transplant patients with BCOR/BCORL1mut prospectively.
There are limitations to this study that should be acknowledged. First, this was a single-center and retrospective study. Second, we could not compare the efficacy of chemotherapy and transplantation due to the lack of chemo-based cohort.
In summary, we are the first to our knowledge to report the comparable transplant outcomes of BCOR- and BCORL1-mutated AML with CK-AML. BCOR- and BCORL1-mutated AML tend to have a higher tendency to relapse, however, which requires further investigation in large-scale multicenter studies.
Acknowledgements
The authors thank AiMi Academic Services (www.aimieditor.com) for English language editing and review services.
Declarations
Ethics approval and consent to participate
All cases were included in the National Longitudinal Cohort of Hematological Diseases (NICHE, NCT04645199) which was approved by the Ethics Committee of IHCAMS. All patients provided informed consent for clinical information for scientific research at the time of first admission.
Consent for publication
All the authors consent for publication.
Competing interests
The authors declare no competing interests.
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