Correction: TP53-mutated myelodysplastic syndromes and acute myeloid leukemia: a comprehensive overview of targeted approaches
Year: 2026
Type: erratum
Abstract: Figure 1: A simplified overview of p53 biology and its regulation in cells with wild-type p53 and mutated p53. Under cellular stress (e.g. DNA damage, oncogene activation, or reactive oxygen species), upstream stress kinases such as ATM, ATR, and JNK phosphorylate p53, disrupting its interaction with negative regulators MDM2 and MDM4. Activated ARF from oncogenic stress binds MDM2 and inhibits it from ubiquitylating p53. Stabilized p53 accumulates in the nucleus to activate transcription of p53 target genes that enforce cell-cycle arrest, trigger apoptosis, and facilitate DNA repair. Wild-type p53 also restrains proliferative/survival signaling by antagonizing the JAK2-STAT3 pathway, in part through induction or activation of negative regulators such as SHP2, thereby reinforcing its tumor-suppressive function. On the other hand, mutant p53 proteins often evade degradation partly through aberrant interactions with molecular chaperones like HSP90. MDM2 is unable to target mutant p53 proteins for degradation. As a result, mutant p53 fails to induce cell-cycle arrest, apoptosis, or DNA repair. Mutant p53-associated dysregulation also leads to ROS accumulation and subsequently impaired SHP2 activity, collectively promoting leukemic cell proliferation and survival. ROS: reactive oxygen species, ATM: ataxia telangiectasia mutated, ATR: ataxia telangiectasia and Rad3-related protein, JNK: c-Jun N-terminal kinase, ARF: alternate reading frame protein, MDM2: mouse double minute 2 homolog, MDM4 (MDMX): MDM4 homolog, SHP2: Src homology region 2 domain-containing phosphatase-2, JAK2: Janus kinase 2, STAT3: signal transducer and activator of transcription 3, HSP90: heat shock protein 90, LOF: loss-of-function, GOF: gain-of-function. Created with BioRender.com.Under normal physiological conditions, p53 functions as a transcription factor with a short halflife and remains largely inactive due to tight regulation by the negative regulators MDM2 (Mouse Double Minute 2) and MDM4 (also known as MDMX). These proteins promote ubiquitination and subsequent proteasomal degradation of p53, maintaining its low basal levels in unstressed cells (30)(31)(32). However, upon exposure to cellular stress, such as DNA damage or oncogenic signaling (33), the p53/MDM2 interaction is disrupted leading to increase in intracellular p53 stabilization. This stabilization is further enhanced through post-translational modifications including phosphorylation, methylation and acetylation (34)(35)(36)(37)(38). The stabilized p53 either induces cell differentiation or activates transcription of genes leading to apoptosis and cell cycle arrest in cells with mutated or damaged DNA. Interestingly, wild-type p53 (WTp53) may be rendered dysfunctional in some cancers, including primary AML, due to overexpression of MDM2 and/or MDM4 (MDMX), which suppresses p53 activity and is associated with inferior outcomes (11). The tumor suppressor P14/ARF positively regulates p53 by inhibiting MDM2, thus preventing p53 degradation and promoting its stabilization. Low P14ARF expression has been linked to poor prognosis in several studies (39)(40)(41). TP53 mutation in MDS/AML TP53 mutations appear in only 5-10% of de novo MDS/AML cases but are far more frequent in secondary AML (18%) and therapy-related AML (30%) (42)(43)(44). These mutations are often associated with complex karyotypes (CK) and monosomal karyotypes (MK) (8,(45)(46)(47), both indicative of genomic instability. TP53 mutations in MDS/AML can be monoallelic or biallelic (48). In this review, we use the term multihit TP53 as an umbrella concept encompassing classical biallelic alterations as well as functional equivalents, including multiple TP53 mutations, high variant allele frequency suggestive of copy-neutral loss of heterozygosity, or cytogenetic loss of chromosome 17p. The term biallelic TP53 is used when structural involvement of both alleles can be directly inferred. This terminology is consistent with contemporary WHO and ICC frameworks and reflects current clinical practice. Approximately 70% of the cases exhibit biallelic alterations, which typically involve a point mutation in one allele and the loss of the second allele through 17p deletion or monosomy 17. In contrast. monoallelic mutations (25-30%) usually consist of a single point mutation, frequently observed in patients with isolated 5q deletion MDS (22,(49)(50)(51). TP53 mutations may also co-occur with other mutations, commonly in TET2 (29%), SF3B1 (27%), ASXL1 (16%), and DNMT3A (16%) which can influence disease progression and treatment outcomes (48). Furthermore, chromothripsis or chromosome shattering (chromosomal rearrangement) ( 52) is a phenomenon involving catastrophic chromosomal rearrangements which can lead to loss of heterozygosity by inactivating the remaining TP53 allele, particularly in cases with 17p deletion (53). This process is closely linked to TP53 mutations, cell cycle dysfunction, and poor prognosis in AML patients featuring complex karyotype (53). It has been recognized that biallelic or "multihit" involvement with multiple mutations or loss of heterozygosity is seen in 44% of MDS patients with TP53 mutations (48). Conversely, in low-risk MDS, about 20% of patients harbor monoallelic mutations alongside 5q deletion. These cases tend to occur in younger individuals and have a less aggressive clinical course than biallelic mutations (54).The prognostic and therapeutic impact of TP53 allelic status has emerged as a key modifier of response. In MDS, patients with monoallelic TP53 mutations-defined as a single mutation without 17p deletion or replacement of the allele with its mutant counterpart (termed copy neutral loss of heterozygosity or CN-LOH)-demonstrate outcomes comparable to TP53 wild-type disease, with a median overall survival of ~2.5 years and 5-year OS around 40% (48). In contrast, multi-hit TP53 alterations, characterized by loss of the second allele via deletion, CN-LOH, or a second mutation, are strongly associated with complex karyotype and poor prognosis, with a median OS of only 8.7 months and 5-year OS consistently <10%, even after intensive chemotherapy or transplant (48). Importantly, standard molecular testing for myeloid malignancies such as NGS gene panels and cytogenetic analyses may fail to detect CN-LOH. To accurately assess TP53-mutant allele status, specialized methods capable of identifying CN-LOH are required. These include expanded gene panels specifically designed to detect TP53 LOH, single-nucleotide polymorphism (SNP) arrays, or whole-genome/exome sequencing (55,56). Detecting a single TP53 mutation having a VAF of greater than or equal to 50% is considered to be presumptive evidence of loss of the wild-type allele or CN-LOH. However, some cases of CN-LOH with low leukemia burden could be missed (55,57). Precisely distinguishing between monoallelic and multihit TP53 alterations is therefore critical for prognosis and treatment planning. The current diagnostic criteria by International Consensus Classification (ICC) classify cases with 10-19% blasts with any TP53 mutation with VAF >10% as high-risk myeloid neoplasms, regardless of whether they meet classic AML or MDS thresholds. Recent updates by both the World Health Organization (WHO, 5 th edition) and ICC emphasize the poor prognosis of biallelic/multihit TP53 mutations in MDS/AML. Such cases are characterized by one or more of the following: two or more TP53 mutations each with a variant allele frequency (VAF) above 10%, VAF ≥ 50%, loss of the wild-type T53 allele (e.g., 17p deletion or monosomy 17), or the presence of a complex karyotype (5). Moreover, higher VAF levels have been correlated with poorer survival outcomes. A multicenter study involving 359 patients with complex karyotype MDS found that those with TP53 mutations and VAF > 40% had a median overall survival of only 0.6 years, significantly lower than those with VAF <40% (1.1 years, p=0.004). Even patients with VAF <40% had worse outcomes than TP53 wild-type patients (1.1 vs 1.5 years, p= 0.001) (8,58). These findings highlight the prognostic impact of VAF and support its integration into future diagnostic and treatment algorithms. Given the strong association between TP53 mutations, genomic instability, and disease evolution, clonal hematopoiesis provides important insight into early leukemogenic events in TP53-mutated MDS and AML. Clonal hematopoiesis is age-associated expansion of hematopoietic cells driven by somatic mutations. Despite small size of the clones, these mutations lead to increased fitness of mutated clones, posing an increased risk of leukemic transformation affecting 0.5-1% carriers/year, particularly TP53 and U2AF1 (59). There is convincing evidence that TP53 mutations in individuals with clonal hematopoiesis of indeterminate potential (CHIP) are associated with increased risk of hematological cancers (60)(61)(62)(63). TP53 mutation is also seen more frequently in CHIP patients who have received prior radiotherapy or cytotoxic chemotherapy (64). Gene mutations like DNMT3A, TET2, ASXL1, SRSF2, CBL and SF3B1 with TP53 mutation are associated with higher risk of leukemia (15,39,65). A recent study showed TP53, NPM1 and SRSF2 as dominant mutations preceding the AML whereas DNMT3A and TET2 mutations were stable over time (61). Therefore, understanding the correlation between clonal hematopoiesis and mechanisms of progression into leukemia remains crucial to design therapies targeting TP53 mutation.For younger and fit patients with AML, standard induction regimens traditionally include cytarabine in combination with an anthracycline, such as the "7+3" regimen or the FLAG-Ida protocol (fludarabine, cytarabine, idarubicin, and G-CSF) (66). However, the patients harboring TP53 mutations consistently demonstrate poor response to standard therapies, including intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT). Outcomes are particularly unfavorable in cases with biallelic TP53 mutations and complex or monosomal karyotypes (CK/MK) (67,68). Multivariant analysis showed that TP53 mutations are independently associated with inferior overall outcomes (OS), reduced disease-free survival (DFS), and lower response rates (RR), irrespective of underlying cytogenetic abnormalities (69). Relapse rates following induction may reach up to 20-30% (53,70), with a median OS in the range of 4-9 months, underscoring the limited efficacy of conventional cytotoxic regimens in this high-risk population (71)(72)(73)(74). Table 1 82) Patients with TP53-mutated AML treated with CPX-351 consistently show lower remission rates, early relapse, and short overall survival, particularly in the presence of multihit TP53 alterations and complex karyotypes. (7,82) Overall, outcomes in this subgroup appear comparable to those achieved with other intensive cytotoxic regimens and remain substantially inferior to those observed in TP53-wild type AML, indicating that CPX-351 does not overcome TP53-associated chemoresistance. ( 29)Hypomethylating agents azacitidine and decitabine are the standard first-line treatments for elderly AML patients and those with high-risk MDS (HR-MDS). Azacitidine is a cytidine analog that after incorporation into DNA acts as a noncompetitive inhibitor of DNA methyltransferase 1 (DNMT1) (88). In the AZA-001 phase III trial, azacitidine was compared with conventional care regimens (best supportive care, low-dose cytarabine, or intensive chemotherapy) in patients with higher-risk myelodysplastic syndromes. Azacitidine significantly prolonged overall survival (median 24.5 vs 15.0 months; HR 0.58), delayed progression to acute myeloid leukemia and was associated with higher rates of hematologic response compared with conventional care (89). In the VIALE-A trial, which compared azacitidine plus venetoclax with azacitidine alone in previously untreated AML patients ineligible for intensive chemotherapy, azacitidine monotherapy was associated with median overall survival of 9.6 months and a composite complete remission (CRc) rate of 28.3% in the overall study population. However, outcomes in the TP53-mutated subgroup were particularly poor, with no observed remissions (CRc 0%) and a median overall survival of approximately 5-6 months, highlighting the minimal clinical benefit of azacitidine alone in this high-risk molecular subset (90). Decitabine, a deoxycytidine analog, functions by causing widespread hypomethylation, restoring expression of silenced tumor suppressors, and induction of DNA damage. Decitabine is currently FDA-approved for the treatment of MDS. However, it has not received FDA approval for AML, as a large randomized international phase III trial comparing decitabine with supportive care and low-dose cytarabine in elderly AML patients demonstrated improved complete remission rates but no statistically significant benefit in overall survival (91). In contrast, decitabine is approved by the European Medicines Agency and is recommended by the NCCN guidelines. Despite the of FDA it to be used for AML in the The clinical trial with decitabine a response rate TP53 mutated cases treated with decitabine regimen compared to in TP53 wild-type patients 0.001) overall survival was months in patients with TP53 mutations and months in those with wild-type TP53 Importantly, these findings were from a study and have not been consistently in subsequent trial including a single phase trial comparing and decitabine regimens in TP53-mutated AML, response rates vs and overall survival vs months; were not significantly between regimens A phase trial demonstrated complete remission rates with decitabine compared to standard care in AML patients with overall survival also decitabine months the not reach (91). in TP53 variant allele frequency treatment has been associated with improved survival and is used as a prognostic particularly in patients to VAF does not consistently VAF ≥ 40% has been linked to inferior outcomes (median OS vs months with a decitabine regimen has but mutation are not such as transplantation a apoptosis by targeting proteins in leukemic blasts It was in the TP53-mutated AML, as was to be of p53 in combination with low therapies or low approval for or patients with AML in (90). studies showed limited benefit of venetoclax in TP53-mutated those with multi-hit TP53 In a phase trial decitabine plus venetoclax in elderly AML, TP53-mutated patients had a median OS of only months, significantly than TP53 wild-type patients months; HR with lower and higher early A large analysis of patients with TP53 mutation AML found no significant in OS vs months, p= or vs when compared to regimens has been in combination with intensive chemotherapy regimens such as FLAG-Ida and In a phase trial, patients with AML received standard induction plus alongside venetoclax for or The combination was well in fit up to years of with no induction and achieved high efficacy complete remission in of patients and in were consistent risk with the of the TP53-mutated subgroup of remission and survival outcomes poor a recent study of intensive chemotherapy plus venetoclax AML patients cytarabine, factor and plus venetoclax achieved a overall response with of patients a composite complete remission and disease by and Importantly, the study patients harboring TP53 mutations with one with 20% and and with and achieved an but remissions were short with median of response of subsequently and with median overall survival of months These highlight that even the regimens may only benefit in multi-hit TP53-mutated AML, underscoring the for in this high-risk hematopoietic stem cell transplant remains the only for patients with TP53-mutated AML and MDS. However, outcomes are poor, with and rates significantly up to compared to TP53 wild-type patients In a recent analysis of patients with TP53-mutated AML or MDS allogeneic TP53 variant allele frequency (VAF) and cytogenetic outcomes TP53 VAF and were the of prognostic patients with TP53 VAF had a of those with TP53 VAF and complex or had a of and patients with TP53 VAF without these abnormalities achieved a of Such that not be treated as a single high-risk transplant in this and often Outcomes are more by TP53 status than by burden remission disease progression in TP53-mutated AML often the leukemia transplant efficacy Importantly, that patients in may significant with reduced and risk In a study comparing allogeneic with in patients with high-risk MDS overall survival was significantly higher years in patients with a compared to those without vs and was lower vs the survival only after the second early Therefore, early of the patients remissions remain critical the limited efficacy of current therapies targeting TP53-mutated are and may as or after A overview of therapeutic in is in Figure 2 is a small that mutant p53 by mutant p53 to its wild-type and function. it is a of which is into the the of in mutant p53, that the protein and its including stress and with azacitidine demonstrated in a phase trial, azacitidine rates of 50% in TP53-mutant MDS and in AML, with molecular remissions VAF in of to in molecular lead to improved survival not vs Despite subsequent more A regimen azacitidine showed a of and a median OS of months, to alone in AML A phase study a median survival of months and a median OS of months, these were from the of the phase 2 was the overall response rate was including with TP53 achieved in was months and median OS Outcomes were in patients or TP53 allogeneic transplantation overall these findings that has not consistently in remission or survival benefit in TP53-mutated a also p53 by to mutant p53 and its tumor-suppressive In to p53 it including 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Source: Frontiers in Oncology
Authors: Shweta Deshpande, Wing Fai Li, Junmin Song, Mark Forsberg, Claudio Cerchione, Giovanni Martinelli, Marina Konopleva
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7135206166
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