Prognostic significance of acquired copy‐neutral loss of heterozygosity in acute myeloid leukemia

The karyotype of bone-marrow cells at the time of diagnosis is one of the most important prognostic factors in patients with myelodysplastic syndromes (MDS). In some cases, the acquisition of additional genetic aberrations (clonal evolution [CE]) associated with clinical progression may occur during the disease. We analyzed a cohort of 469 MDS patients using a combination of molecular cytogenomic methods to identify cryptic aberrations and to assess their potential role in CE. We confirmed CE in 36 (8%) patients. The analysis of bone-marrow samples with a combination of cytogenomic methods at diagnosis and after CE identified 214 chromosomal aberrations. The early genetic changes in the diagnostic samples were frequently MDS specific (17 MDS-specific/57 early changes). Most progression-related aberrations identified after CE were not MDS specific (131 non-MDS-specific/155 progressionrelated changes). Copy number neutral loss of heterozygosity (CN-LOH) was detected in 19% of patients. MDS-specific CN-LOH (4q, 17p) was identified in three patients, and probably pathogenic homozygous mutations were found in TET2 (4q24)and TP53 (17p13.1) genes. We observed a statistically significant difference in overall survival (OS) between the groups of patients divided according to their diagnostic cytogenomic findings, with worse OS in the group with complex karyotypes (P = .021). A combination of cytogenomic methods allowed us to detect many cryptic genomic changes and identify genes and genomic regions that may represent therapeutic targets in patients with progressive MDS.

Section: Microarray Analysissupporting

confidence: 92%

Cryptic aberrations may allow more accurate prognostic classification of patients with myelodysplastic syndromes and clonal evolution

Svobodova

Lhotska

Hodanova

et al. 2020

“…Patient 1 in the present study showed a karyotype with isolated t(7;21); however, GMA identified cnLOH of 11p in 25% of the sample, which was consistent with the tumor burden detected by flow cytometry. 11p is reported as one of the most common sites of acquired cnLOH in AML patients, presenting with impacts on the overall survival rate and recurrence risk . As coincident findings in AML with t(7;21), del(5q) and cnLOH 11p may be linked to the variability in clinical and pathological manifestations.…”

Section: Discussionmentioning

confidence: 89%

“…11p is reported as one of the most common sites of acquired cnLOH in AML patients, presenting with impacts on the overall survival rate and recurrence risk. 24 As coincident findings in AML with t (7;21), del(5q) and cnLOH 11p may be linked to the variability in clinical and pathological manifestations. Alternatively, they may act as second hit mutations to the initiating event t(7;21) in leukemia.…”

Section: Discussionmentioning

confidence: 90%

Pediatric acute myeloid leukemia with t(7;21)(p22;q22)

Paulraj

Diamond

Razzaqi

et al. 2019

The t(7;21)(p22;q22) resulting in RUNX1‐USP42 fusion, is a rare but recurrent cytogenetic abnormality associated with acute myeloid leukemia (AML) and myelodysplastic syndromes. The prognostic significance of this translocation has not been well established due to the limited number of patients. Herein, we report three pediatric AML patients with t(7;21)(p22;q22). All three patients presented with pancytopenia or leukopenia at diagnosis, accompanied by abnormal immunophenotypic expression of CD7 and CD56 on leukemic blasts. One patient had t(7;21)(p22;q22) as the sole abnormality, whereas the other two patients had additional numerical and structural aberrations including loss of 5q material. Fluorescence in situ hybridization analysis on interphase cells or sequential examination of metaphases showed the RUNX1 rearrangement and confirmed translocation 7;21. Genomic SNP microarray analysis, performed on DNA extracted from the bone marrow from the patient with isolated t(7;21)(p22;q22), showed a 32.2 Mb copy neutral loss of heterozygosity (cnLOH) within the short arm of chromosome 11. After 2‐4 cycles of chemotherapy, all three patients underwent allogeneic hematopoietic stem cell transplantation (HSCT). One patient died due to complications related to viral reactivation and graft‐versus‐host disease. The other two patients achieved complete remission after HSCT. Our data displayed the accompanying cytogenetic abnormalities including del(5q) and cnLOH of 11p, the frequent pathological features shared with other reported cases, and clinical outcome in pediatric AML patients with t(7;21)(p22;q22). The heterogeneity in AML harboring similar cytogenetic alterations may be attributed to additional uncovered genetic lesions.

“…91 However, this heterozygous status is unstable, and loss of heterozygosity (LOH) frequently follows in malignant progression and holds prognostic impact. 92,93 LOH is indicative of pressure to inactivate the remaining TP53 allele and is found in t-AML, AML postmyeloproliferative Philadelphia1 (Ph1)-negative neoplasms, and LFSrelated AML. 6,18,94 Missense mutations of TP53 frequently yield LOF phenotypes, abrogating sequence-specific DNA-binding activity toward TP53 responsive elements.…”

Section: Aml-related Tp53 Mutationsmentioning

confidence: 99%

The role of TP53 in acute myeloid leukemia: Challenges and opportunities

Barbosa

Adams

et al. 2019

The tumor suppressor gene TP53 is one of the most frequently mutated genes in human cancer. The central role of the TP53 protein in several fundamental processes such as cancer, aging, senescence, and DNA repair has ensured enormous attention. However, the role of TP53 in acute myeloid leukemia (AML) is enigmatic. Unlike many other human cancers, a vast majority of AMLs display no genomic TP53 alterations. There is now growing appreciation of the fact that the unaltered TP53 status of tumor cells can be exploited therapeutically. As most AMLs have an intact TP53 gene, its physiological tumor‐suppressive roles could be harnessed. Therefore, the use of pharmacological activators of the TP53 pathway may provide clinical benefit in AML. Conversely, even though the frequency of TP53 mutations in AML is substantially lower than in other human cancers, TP53 mutations are associated with chemoresistance and high risk of relapse. In patients with TP53 mutations, these alterations may lead to novel, selective vulnerabilities, creating opportunities for therapeutic targeting of TP53 mutant AML. The mutational status of TP53 therefore poses challenges and opportunities in terms of advancing effective treatment strategies in AML. An increasing armamentarium of small‐molecule activators of the TP53 pathway, and a growing understanding of molecular pathways triggered by mutant TP53 have accelerated efforts aimed at targeting TP53 function in AML. In combination with standard AML chemotherapy or emerging targeted therapies, pharmacological targeting of the TP53 pathway may provide therapeutic benefit in AML.