A frequent nonsense mutation in exon 1 across certain HLA-A and -B alleles in leukocytes of patients with acquired aplastic anemia

Mizumaki, Hiroki; Hosomichi, Kazuyoshi; Hosokawa, Kohei; Yoroidaka, Takeshi; Imi, Tatsuya; Zaimoku, Yoshitaka; Katagiri, Takamasa; Nguyễn, Mai Ánh; Tran, Dung Cao; El-Badry, Mahmoud; Chonabayashi, Kazuhisa; Yoshida, Yoshinori; Takamatsu, Hiroyuki; Ozawa, Tatsuhiko; Azuma, Fumihiro; Kishi, Hiroyuki; Fujii, Yoichi; Ogawa, Seishi; Tajima, Atsushi; Nakao, Shinji

doi:10.3324/haematol.2020.247809

Cited by 19 publications

(9 citation statements)

References 33 publications

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“…However, loss of HLA-B*40:02 and certain minor alleles was related to higher blood counts and all patients who lost these alleles responded to IST (Supplemental Figure 16; Supplemental Table 5). These relationships are consistent with the predictive value of reticulocytes for IST response, 40,41 and the generally high response rate to IST in Japanese patients with HLA loss, in whom HLA-B*40:02 was most frequently inactivated, 18,42 but HLA-B*14:02 and HLA-B*08:01 genotypes are virtually absent. 43 High-risk clonal evolution was correlated with the most frequently inactivated allele HLA-B*14:02 (P = .0092; Figure 3A), as previously suggested by Babushok et al, 19 and with HLA loss (P = .00040; Figure 3B), especially with loss of HLA-A*02:01 and HLA-B*14:02 (Supplemental Figure 17A; Supplemental Table 5).…”

Section: Clinical Significance Of Hla Class I Allele Loss and Individual Allelessupporting

confidence: 79%

HLA associations, somatic loss of HLA expression, and clinical outcomes in immune aplastic anemia

Zaimoku

Patel

Adams

et al. 2021

Blood

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Immune aplastic anemia (AA) features somatic loss of HLA class I allele expression on bone marrow cells, consistent with a mechanism of escape from T cell-mediated destruction of hematopoietic stem and progenitor cells. The clinical significance of HLA abnormalities has not been well characterized. We examined somatic loss of HLA class I alleles, and correlated HLA loss and mutation-associated HLA genotypes with clinical presentation and outcomes after immunosuppressive therapy in 544 AA patients. HLA class I allele loss was detected in 92 (22%) of the 412 patients tested, in whom there were 393 somatic HLA gene mutations and 40 instances of loss of heterozygosity. Most frequently affected was HLA-B*14:02, followed by HLA-A*02:01, HLA-B*40:02, HLA-B*08:01, and HLA-B*07:02. HLA-B*14:02, HLA-B*40:02, and HLA-B*07:02 were also overrepresented in AA. High-risk clonal evolution was correlated with HLA loss, HLA-B*14:02 genotype, and older age, which yielded a valid prediction model. In two patients, we traced monosomy 7 clonal evolution from preexisting clones harboring somatic mutations in HLA-A*02:01 and HLA-B*40:02. Loss of HLA-B*40:02 correlated with higher blood counts. HLA-B*07:02 and HLA-B*40:01 genotypes and their loss correlated with late onset of AA. Our results suggest the presence of specific immune mechanisms of molecular pathogenesis with clinical implications. HLA genotyping and screening for HLA loss may be of value in the management of immune AA. This study was registered at clinicaltrials.gov as NCT00001964, NCT00061360, NCT00195624, NCT00260689, NCT00944749, NCT01193283, and NCT01623167.

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Section: Clinical Significance Of Hla Class I Allele Loss and Individual Allelessupporting

confidence: 79%

HLA associations, somatic loss of HLA expression, and clinical outcomes in immune aplastic anemia

Zaimoku

Patel

Adams

et al. 2021

Blood

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“…24 Similarly, somatic hits in the human leukocyte antigen (HLA) genomic region have also been identified in AA and tentatively assigned to an immune escape of the stressed BM, paralleling findings observed in cancer. 16,17,25-27…”

Section: Introductionmentioning

confidence: 99%

Clinical and Molecular Determinants of Clonal Evolution in Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria

Gurnari

Pagliuca

Prata

et al. 2023

JCO

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PURPOSE Secondary myeloid neoplasms (sMNs) remain the most serious long-term complications in patients with aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH). However, sMNs lack specific predictors, dedicated surveillance measures, and early therapeutic interventions. PATIENTS AND METHODS We studied a multicenter, retrospective cohort of 1,008 patients (median follow-up 8.6 years) with AA and PNH to assess clinical and molecular determinants of clonal evolution. RESULTS Although none of the patients transplanted upfront (n = 117) developed clonal complications (either sMN or secondary PNH), the 10-year cumulative incidence of sMN in nontransplanted cases was 11.6%. In severe AA, older age at presentation and lack of response to immunosuppressive therapy were independently associated with increased risk of sMN, whereas untreated patients had the highest risk among nonsevere cases. The elapsed time from AA to sMN was 4.5 years. sMN developed in 94 patients. The 5-year overall survival reached 40% and was independently associated with bone marrow blasts at sMN onset. Myelodysplastic syndrome with high-risk phenotypes, del7/7q, and ASXL1, SETBP1, RUNX1, and RAS pathway gene mutations were the most frequent characteristics. Cross-sectional studies of clonal dynamics from baseline to evolution revealed that PIGA/human leukocyte antigen lesions decreased over time, being replaced by clones with myeloid hits. PIGA and BCOR/L1 mutation carriers had a lower risk of sMN progression, whereas myeloid driver lesions marked the group with a higher risk. CONCLUSION The risk of sMN in AA is associated with disease severity, lack of response to treatment, and patients' age. sMNs display high-risk morphological, karyotypic, and molecular features. The landscape of acquired somatic mutations is complex and incompletely understood and should be considered with caution in medical management.

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“…Acquired aplastic anemia (AA) is a syndrome characterized by pancytopenia and bone marrow (BM) hypoplasia without apparent dysplasia in the BM cells and an increase in the number of blasts [1]. As the main pathophysiology of AA is a reduction of hematopoietic stem progenitor cells (HSPCs) due to T-cell attacks against HSPCs, HSPCs themselves are thought to be healthy and give rise to polyclonal hematopoiesis [2][3][4][5]. However, recent studies using next-generation sequencing have revealed that approximately one third of newly diagnosed AA patients have clonal hematopoiesis by HSPCs with somatic mutations of myeloid malignancy-related genes [6,7].…”

Section: Introductionmentioning

confidence: 99%

“…Different from murine HSPCs that can be marked by transduced genes, it is generally impossible to know which HSPCs do or do not contribute to hematopoiesis due to a lack of useful markers on healthy HSPCs, which are responsible for active hematopoiesis. Rare exceptions include HLA class I allelelacking (HLA[−]) HSPCs, which are detected in approximately 30% of AA patients [4,5,12]. HLA(−) HSPCs are thought to be healthy HSPCs that escape T-cell attack due to the lack of particular HLA-class I alleles that present autoantigens of HSPCs to T cells in AA [13,14].…”

Section: Introductionmentioning

confidence: 99%

Hematopoietic stem progenitor cells with malignancy‐related gene mutations in patients with acquired aplastic anemia are characterized by the increased expression of CXCR4

Katagiri

Espinoza

Uemori

et al. 2022

eJHaem

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The phenotypic changes in hematopoietic stem progenitor cells (HSPCs) with somatic mutations of malignancy-related genes in patients with acquired aplastic anemia (AA) are poorly understood. As our initial study showed increased CXCR4 expression on HLA allele-lacking (HLA[−]) HSPCs that solely support hematopoiesis in comparison to redundant HLA(+) HSPCs in AA patients, we screened the HSPCs of patients with various types of bone marrow (BM) failure to investigate their CXCR4 expression.

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A frequent nonsense mutation in exon 1 across certain HLA-A and -B alleles in leukocytes of patients with acquired aplastic anemia

Cited by 19 publications

References 33 publications

HLA associations, somatic loss of HLA expression, and clinical outcomes in immune aplastic anemia

HLA associations, somatic loss of HLA expression, and clinical outcomes in immune aplastic anemia

Clinical and Molecular Determinants of Clonal Evolution in Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria

Hematopoietic stem progenitor cells with malignancy‐related gene mutations in patients with acquired aplastic anemia are characterized by the increased expression of CXCR4

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