How we treat Richter syndrome

Richter syndrome (RS) is defined as the transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). RS occurs in approximately 2% to 10% of CLL patients during the course of their disease, with a transformation rate of 0.5% to 1% per year. A combination of germline genetic characteristics, clinical features (eg, advanced Rai stage), biologic (ζ-associated protein-70+, CD38+, CD49d+) and somatic genetic (del17p13.1 or del11q23.1) characteristics of CLL B cells, and certain CLL therapies are associated with higher risk of RS. Recent studies have also identified the crucial role of CDKN2A loss, TP53 disruption, C-MYC activation, and NOTCH1 mutations in the transformation from CLL to RS. An excisional lymph node biopsy is considered the gold standard for diagnosis of RS; a 18F-fluorodeoxyglucose positron emission tomography scan can help inform the optimal site for biopsy. Approximately 80% of DLBCL cases in patients with CLL are clonally related to the underlying CLL, and the median survival for these patients is approximately 1 year. In contrast, the remaining 20% of patients have a clonally unrelated DLBCL and have a prognosis similar to that of de novo DLBCL. For patients with clonally related DLBCL, induction therapy with either an anthracycline- or platinum-based regimen is the standard approach. Postremission stem cell transplantation should be considered for appropriate patients. This article summarizes our approach to the clinical management of CLL patients who develop RS.

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Genetic lesions associated with chronic lymphocytic leukemia transformation to Richter syndrome

Journal of Experimental Medicine ◽

10.1084/jem.20131448 ◽

2013 ◽

Vol 210 (11) ◽

pp. 2273-2288 ◽

Cited By ~ 143

Author(s):

Giulia Fabbri ◽

Hossein Khiabanian ◽

Antony B. Holmes ◽

Jiguang Wang ◽

Monica Messina ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

De Novo ◽

B Cell Lymphoma ◽

Lymphocytic Leukemia ◽

Aggressive Lymphoma ◽

Richter Syndrome ◽

Whole Exome ◽

Genomic Landscape ◽

Distinct Disease

Richter syndrome (RS) derives from the rare transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, most commonly of the diffuse large B cell lymphoma (DLBCL) type. The molecular pathogenesis of RS is only partially understood. By combining whole-exome sequencing and copy-number analysis of 9 CLL-RS pairs and of an extended panel of 43 RS cases, we show that this aggressive disease typically arises from the predominant CLL clone by acquiring an average of ∼20 genetic lesions/case. RS lesions are heterogeneous in terms of load and spectrum among patients, and include those involved in CLL progression and chemorefractoriness (TP53 disruption and NOTCH1 activation) as well as some not previously implicated in CLL or RS pathogenesis. In particular, disruption of the CDKN2A/B cell cycle regulator is associated with ∼30% of RS cases. Finally, we report that the genomic landscape of RS is significantly different from that of de novo DLBCL, suggesting that they represent distinct disease entities. These results provide insights into RS pathogenesis, and identify dysregulated pathways of potential diagnostic and therapeutic relevance.

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Biology and treatment of Richter syndrome

Blood ◽

10.1182/blood-2018-01-791376 ◽

2018 ◽

Vol 131 (25) ◽

pp. 2761-2772 ◽

Cited By ~ 42

Author(s):

Davide Rossi ◽

Valeria Spina ◽

Gianluca Gaidano

Keyword(s):

Cell Lymphoma ◽

Clinical Signs ◽

B Cell Lymphoma ◽

Signs And Symptoms ◽

Lymphocytic Leukemia ◽

Aggressive Lymphoma ◽

Large B Cell Lymphoma ◽

Richter Syndrome ◽

Positron Emission ◽

Clinical Signs And Symptoms

AbstractRichter syndrome (RS) is the development of an aggressive lymphoma in patients with chronic lymphocytic leukemia (CLL). Two pathologic variants of RS are recognized: namely, the diffuse large B-cell lymphoma (DLBCL) variant and the rare Hodgkin lymphoma (HL) variant. Histologic documentation is mandatory to diagnose RS. The clinical suspicion of RS should be based on clinical signs and symptoms. Differential diagnosis between CLL progression and RS and choice of the biopsy site may take advantage of positron emission tomography/computed tomography. Molecular lesions of regulators of proliferation (CDKN2A, NOTCH1, MYC) and apoptosis (TP53) overall associate with ∼90% of DLBCL-type RS, whereas the biology of the HL-type RS is largely unknown. The prognosis of the DLBCL-type RS is unfavorable; the outcome of HL-type RS appears to be better. The most important RS prognostic factor is the clonal relationship between the CLL and the aggressive lymphoma clones, with clonally unrelated RS having a better prognosis. Rituximab-containing combination chemotherapy for DLBCL is the most widely used treatment in DLBCL-type RS. Fit patients who respond to induction therapy should be offered stem cell transplantation (SCT) to prolong survival. Adriamycin, bleomycin, vinblastine, and dacarbazine is the preferred regimen for the HL-type RS, and SCT consolidation is less used in this condition.

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SNP-Arrays Provide New Insights Into the Pathogenesis of Richter Syndrome (RS)

Blood ◽

10.1182/blood.v118.21.263.263 ◽

2011 ◽

Vol 118 (21) ◽

pp. 263-263

Author(s):

Andrea Rinaldi ◽

Ekaterina Chigrinova ◽

Ivo Kwee ◽

Davide Rossi ◽

Paola MV Rancoita ◽

...

Keyword(s):

Copy Number ◽

De Novo ◽

Conflicts Of Interest ◽

B Cell Lymphoma ◽

Large Series ◽

Lymphocytic Leukemia ◽

Aggressive Lymphoma ◽

Rank Test ◽

Dna Copy Number ◽

Poor Overall Survival

Abstract Abstract 263 RS represents the development of a diffuse large B-cell lymphoma (DLBCL) in the context of chronic lymphocytic leukemia (CLL). The pathogenesis of RS is still largely unknown. Analysis of RS has been often focused on the study of lesions previously identified in de novo DLBCL. However, we have previously shown that RS lacks many of the typical genetic lesions shown in DLBCL (Rossi et al, Blood 2011). Here, we have applied an unbiased, genome-wide approach, searching for DNA copy number alterations in a large series of RS, comparing them with de novo DLBCL, CLL-phase of RS and untransformed CLL. Methods. The study included 50 RS, 30 CLL-phases preceding RS, 100 DLBCL, 318 CLL. All RS were classified as DLBCL. DNA was extracted from frozen biopsies and was processed using the Affymetrix GeneChip Human Mapping SNP6 arrays. Differences in frequencies between subgroups were evaluated using Fisher's exact test. Clinical data were available in half of the cases and genomic lesions were evaluated for their impact on clinical outcome with the log-rank test. Results. In RS, the most common gains were +12 (40%), +4q12 (14%), +2p25.3-25.2 (13%), +8q23.3-qter (12%), +1q32.1, +2p16.1-13.2 (BCL11A/REL), +15q22.31-26.3, +18q21.33 (BCL2) (10%), and +3q24.1-q26.3 (9%). Amplifications were observed at the BCL2 locus and at 1q32.1. The most common losses were at 17p13.1 (TP53; 29%), 8p21.3 (TNFRSF10A/B; 15%), 8p23.3 (16%), 11q22.3 (ATM) (15%), 14q23.3 (13%), 7q33–35 (11%), 14q32.11 (10%), 14q32.31-32.33 (TRAF3), and 9p21.3 (CDKN2A) (9%). The latter locus was also the target of recurrent homozygous deletions. RS appeared intermediate between CLL-phase and de novo DLBCL in terms of number of recurrent lesions. When compared with de novo DLBCL, RS presented less -6q23 (TNFAIP3; P=2.54E-05), -15q15.1-q21.1 (B2M) (P=5.64E-04), +7/7q (P=5.71E-04), -6q21 (PRDM1; P=6.53E-04), +2p16.1 (BCL11A; P=3.22E-03), -1p36 (TNFRSF14; P 9.57E-03), copy-neutral LOH at 6p25.3-21.32 (P =1.01E-02), +5p (P=1.39E-02), +11q14.1-q25 (P=1.63E-02), +1q22-q41 (P 2.13E-02), +6p21 (P 2.48E-02). Conversely, RS presented more often +4q12 (P=8.96E-03), -7q33-35 (P=2.04E-02), -11q22.3 (ATM; P=2.14E-02), -14q23.3 (P=2.69E-02). No statistical differences were observed for lesions such as +3/+3q, +8q, -8p, - 9p21.3 (CDKN2A), +12q, +15q, -17p (TP53). Compared to CLL-phase, RS had significantly more gains at 1q32.1 (P=2.28E-02), 11q23.3 (P=5.38E-03), 11q24 (P=1.10E-02) and 9p21.3 losses (CDKN2A; P=1.10E-02). Compared to the large series of CLL with no history of transformation, CLL-phase samples presented less frequently losses at 13q14.3 (DLEU2, MIR15A, MIR16-1a; 6.58E-03), more commonly gains at 12 (P=2.66E-02), 4q12 (P=1.103E-02), +2p (P=2.97E-02), and loss at TP53 locus (P=2.23E-03). The presence of losses of CDKN2A (P=4.6E-03), TNFRSF10A/B (P=3.2E-02) and BCL2 gains (P=4.0E-02) determined a poor overall survival in RS. Conclusions. DNA copy number changes in RS are intermediate between de novo DLBCL and CLL-phase. Recurrent lesions were identified that appeared more common in RS than in DLBCL, and that seem to be involved in the progression from CLL to an aggressive lymphoma. Also, the acquisition of mono- and bi-allelic losses of CDKN2A appears as one of the most important event in the transition from CLL-phase to RS. CDKN2A and TNFRSF10A/B losses and BCL2 gains were associated with a poor outcome. AR & EC equally contributed to the work. Disclosures: No relevant conflicts of interest to declare.

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Richter transformation in the era of novel agents

Hematology ◽

10.1182/asheducation-2018.1.256 ◽

2018 ◽

Vol 2018 (1) ◽

pp. 256-263 ◽

Cited By ~ 4

Author(s):

Wei Ding

Keyword(s):

B Cell ◽

De Novo ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Lymphocytic Leukemia ◽

Novel Agents ◽

Aggressive Lymphoma ◽

Management Approach ◽

Large B Cell Lymphoma ◽

Large B Cell

AbstractRecent approvals of several oral targeted agents have revolutionized chronic lymphocytic leukemia (CLL) therapy. However, CLL patients continue to progress; particularly, 4% to 20% of previously treated CLL patients undergo transformation into high-grade lymphoma. Richter transformation is defined as a transformation of CLL into aggressive lymphoma, most commonly diffuse large B-cell lymphoma. These patients typically have poor response to traditional chemotherapy used to treat de novo diffuse large B-cell lymphoma and similar or shorter overall survival (median 3-11 months) in the era of novel agents. Here, I review the contemporary literature on Richter transformation, particularly in the context of novel agents used in CLL, and discuss the management approach for these patients.

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Unusual Extramedullary Plasmacytoma: A Rare but Possible Cause of Lymphadenopathy in Chronic Lymphocytic Leukemia

Case Reports in Medicine ◽

10.1155/2015/657049 ◽

2015 ◽

Vol 2015 ◽

pp. 1-3 ◽

Cited By ~ 1

Author(s):

S. P. Chantepie ◽

Q. Cabrera ◽

J. B. Mear ◽

V. Salaun ◽

E. Lechapt-Zalcman ◽

...

Keyword(s):

Lymph Node ◽

Chronic Lymphocytic Leukemia ◽

Lymph Node Biopsy ◽

Extramedullary Plasmacytoma ◽

Lymphocytic Leukemia ◽

Aggressive Lymphoma ◽

Tonsillar Hypertrophy ◽

Richter Syndrome ◽

Frequent Event ◽

Possible Cause

Cervical bilateral lymphadenopathy is a frequent event during chronic lymphocytic leukemia (CLL) natural history. However, lymph node biopsy is generally not required as long as transformation into an aggressive lymphoma (Richter syndrome) is not suspected. We present here a rare case of CLL patient who developed progressive bilateral cervical lymph node and bilateral tonsillar hypertrophy. CLL front-line therapy was ineffective leading to adenectomy and diagnosis of concomitant extramedullary plasmacytoma. Radiotherapy did not result in the disappearance of lymphadenopathy. Adenectomy should be performed in CLL cases to avoid misdiagnosis.

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Ibrutinib Treatment of a Patient with Relapsing Chronic Lymphocytic Leukemia and Sustained Remission of Richter Syndrome

Tumori Journal ◽

10.5301/tj.5000667 ◽

2017 ◽

Vol 103 (1_suppl) ◽

pp. S37-S40 ◽

Cited By ~ 3

Author(s):

Elisa Albi ◽

Stefano Baldoni ◽

Patrizia Aureli ◽

Erica Dorillo ◽

Beatrice Del Papa ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Kinase Inhibitor ◽

Rare Event ◽

Lymphocytic Leukemia ◽

Sustained Remission ◽

Richter Syndrome ◽

Positron Emission ◽

Bruton Tyrosine Kinase ◽

Tomography Scan

Purpose Richter syndrome (RS) is a rare event in chronic lymphocytic leukemia (CLL) that is influenced by biological factors and prior CLL treatments. Ibrutinib is a Bruton tyrosine kinase inhibitor that has shown remarkable efficacy in CLL; however, little is known about its relationship to RS. We report a case of ibrutinib efficacy against CLL in a patient with prolonged remission of RS. Methods The patient was diagnosed with CLL in 2003. Biological findings at onset included absent ZAP70 expression, mutated IGVH, and NOTCH1 mutation. He was treated with FCR with partial response. In 2013, he progressed to RS, not clonally related to the underlying CLL. The patient was treated with anthracycline- and platinum-based regimens, obtaining a complete remission. After 3 years, he presented a CLL progression with worsening lymphocytosis, anemia, thrombocytopenia, increased splenomegaly, and lymphadenopathies. Positron emission tomography-computed tomography scan excluded pathologic uptake. Thus, he was started on ibrutinib. Results At 12 months’ follow-up, we observed white blood cell normalization, increased hemoglobin and platelet levels, disappearance of lymphadenopathy, and spleen size reduction. Therapy was well-tolerated with no evidence of RS. Conclusion This case demonstrates sustained RS remission in a patient with CLL under ibrutinib therapy, thus improving our knowledge on the use of this new drug in CLL and beyond.

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De Novo CD5+ Diffuse Large B-Cell Lymphomas Express VH Genes With Somatic Mutation

Blood ◽

10.1182/blood.v91.4.1145 ◽

1998 ◽

Vol 91 (4) ◽

pp. 1145-1151 ◽

Cited By ~ 66

Author(s):

Masanori Taniguchi ◽

Kouji Oka ◽

Atsunori Hiasa ◽

Motoko Yamaguchi ◽

Toshiyuki Ohno ◽

...

Keyword(s):

B Cell ◽

De Novo ◽

Cell Lymphoma ◽

Variable Region ◽

B Cell Lymphoma ◽

Lymphocytic Leukemia ◽

Cellular Origin ◽

Vh Gene ◽

Vh Genes ◽

Large B Cell

Abstract To clarify the cellular origin of de novo CD5+ diffuse large B-cell lymphoma (CD5+ DLBL), particularly in comparison with other CD5+ B-cell neoplasms such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), we analyzed the nucleotide sequence of the Ig heavy chain variable region (IgVH) genes of de novo CD5+ DLBL cases. All 4 cases examined had extensive somatic mutations in contrast with CLL or MCL. The VH gene sequences of de novo CD5+ DLBL displayed 86.9% to 95.2% homology with the corresponding germlines, whereas those of simultaneously analyzed CLL and MCL displayed 97.6% to 100% homology. The VH family used was VH3 in 1 case, VH4 in 2 cases, and VH5 in 1 case. In 2 of 4 examined cases, the distribution of replacement and silent mutations over the complementarity determining region and framework region in the VH genes was compatible with the pattern resulting from the antigen selection. Clinically, CD5+DLBL frequently involved a variety of extranodal sites (12/13) and lymph node (11/13). Immunophenotypically, CD5+ DLBL scarcely expressed CD21 and CD23 (3/13 and 2/13, respectively). These findings indicate that de novo CD5+ DLBL cells are derived from a B-1 subset distinct from those of CLL or MCL.

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Radioimmunotherapy (RIT) with 90Y-Ibritumomab Tiuxetan (Zevalin) for the Treatment of Relapsed or Resistant Aggressive Diffuse Large B-Cell Lymphoma (DLBCL) Heavily Pretreated with Rituximab + Chemotherapy: A GIMURELL Experience.

Blood ◽

10.1182/blood.v110.11.4478.4478 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4478-4478 ◽

Cited By ~ 3

Author(s):

Barbara Botto ◽

Marilena Bellò ◽

Giulia Benevolo ◽

Maria Giuseppina Cabras ◽

Claudia Castellino ◽

...

Keyword(s):

De Novo ◽

Cell Lymphoma ◽

Bone Marrow Involvement ◽

B Cell Lymphoma ◽

Aggressive Lymphoma ◽

Ibritumomab Tiuxetan ◽

Large B Cell Lymphoma ◽

Heavily Pretreated ◽

Previously Treated ◽

Grade Iii

Abstract Introduction: The addition of antibody monoclonal anti CD20 Rituximab to CHOP chemotherapy has resulted in improved CR, progression free survival and overall survival rates for patients affected by diffuse large B cell lymphoma. Recently, RIT with Zevalin has been shown effective in the treatment of relapsed refractory elderly DLBCL. We report the results of a study to evaluate the efficacy and safety of Zevalin in relapsed or chemoresistant aggressive lymphoma previously treated with Rituximab. Patients and methods: Elegibility criteria were as follows: age over 18 years, refractory or chemoresistant CD20+ aggressive lymphoma (grade III follicular, PML or DLBCL de novo) WHO performance status of 0 to 2, stage II bulky, III or IV, bone marrow involvement < 25%, written informed consent in accordance with institutional guidelines. All patients were previously treated with Rituximab and almost two lines of chemotherapy. Patients with pre-treatment platelet counts of > 150.000/mm3 received Zevalin at 0.4 mCi/kg whereas those with platelets < 150.000/mm3 received 0.3 mCi/kg. Results: Fourteen patients were treated with RIT: 5 patients were stage II, 3 stage III, 6 stage IV (5 with bone marrow involvement). Six patients had grade III follicular, 4 primary mediastinal and 4 DLBCL de novo. Ten patients received 0.4 mCi/kg and 4 patients 0.3 mCi/kg. Five chemoresistant patients after 2 or more lines chemoimmunotherapy received RIT in combination with BEAM and subsequent autologous stem cell transplantation (ASCT) and 9 patients were treated with Zevalin alone. Two months after RIT we reported CR 4 patients, PR 5 patients and no response/progression 5 patients (ORR 9/14 patients 64%). All 5 patients treated with RIT + BEAM + ASCT achieved a response (CR 2 patients and PR 3 patients ORR 100%). ORR in 9 patients treated with RIT alone was 46% (CR 2 patients and PR 2 patients). No toxic deaths were observed, two patients died of lymphoma (one patients 1 year after Zevalin infusion and the second progressed and died 5 months after RIT). The most common grade 3–4 AE were neutropenia and thrombocytopenia. Discussion: RIT with 90Y-Ibritumomab Tiuxetan is a safe and effective approach for patients affected by aggressive lymphoma and heavily pretreated with Rituximab + chemotherapy. The effective role of RIT alone or in combination with high dose chemotherapy + ASCT as salvage therapy has to be studied in this subset of patients.

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Heritable Predisposition To Richter Syndrome In Patients With Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v122.21.2867.2867 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2867-2867 ◽

Cited By ~ 3

Author(s):

Sameer A. Parikh ◽

Susan L Slager ◽

Kari G. Rabe ◽

Neil E. Kay ◽

James R Cerhan ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Research Funding ◽

B Cell Lymphoma ◽

Lymphocytic Leukemia ◽

Chromosome 18 ◽

Richter Syndrome ◽

Increased Risk ◽

Translocation Breakpoints

Abstract Background Approximately 2-8% patients with chronic lymphocytic leukemia (CLL) will transform to diffuse large B-cell lymphoma (DLBCL, Richter syndrome [RS]). Clinical characteristics and molecular markers at the time of CLL diagnosis are associated with the risk of RS; however, there are no data regarding germline genetic variations and the risk of RS. Genomewide association studies (GWAS) have shown several single-nucleotide polymorphisms (SNPs) that are associated with a higher risk of familial CLL. It is not known whether any of these polymorphisms also predispose to RS. Methods Since 2002, all consecutive patients with newly diagnosed (<9 months diagnosis) CLL at Mayo Clinic were offered enrollment into a prospective genetic epidemiology study. Patients completed extensive epidemiologic questionnaires and baseline clinical, laboratory, and biologic data were abstracted using a standard protocol. Genotyping of germline tissue at diagnosis was performed using an Illumina iSelect panel and Affymetrix 6.0 SNP chip. All patients were prospectively and longitudinally followed at defined time-points with systematic collection of data on treatments, second cancers, and RS. All patients with biopsy-proven DLBCL during follow-up were considered to have undergone transformation into RS. Time to RS was calculated from CLL diagnosis date until RS or until last follow-up date for those with no RS. SNPs were modeled in two ways: ordinal and dominant. Cox regression was used to estimate hazard ratio (HR) for individual SNPs with time to transformation. Results Thirteen of the GWAS-discovered SNPs associated with risk of developing CLL were available and genotyped on 620 CLL patients. Median age at diagnosis of CLL was 62 years (range 27-88), and 428 (69%) were male. Three hundred and ten (51%) patients were low (0) Rai stage, 271 (45%) were intermediate (I-II) Rai stage, and 22 (4%) were advanced (III-IV) Rai stage. The immunoglobulin heavy chain gene was unmutated in 189 (40%) patients; 157 (32%) patients expressed ZAP-70, 163 (29%) expressed CD38 and 104 (31%) expressed CD49d. Fluorescence in-situ hybridization (FISH) revealed that 210 (41%) patients had del13q, 90 (18%) patients had trisomy 12, 37 (7%) had del11q, 23 (5%) had del17p and 141 (28%) had no detectable FISH abnormalities. As of last follow-up, 239 (39%) patients received therapy for CLL. After a median follow-up of 5.9 years (range 0-11), 15 (2.4%) patients developed biopsy-proven RS. The median time to RS in these 15 patients was 4.5 years (range 1.0-8.7 years). The ordinal HR for the 13 SNPs tested, their corresponding genes, and p-values are shown in Table 1. Germline polymorphisms in a single SNP, rs4987852, encoding for BCL2 (chromosome 18), was significantly associated with an increased risk of RS (ordinal HR=3.9; 95% CI=1.6-9.8; p-value=0.004). This allele was present in 48/605 (8%) non-transformed CLL patients compared to 4/15 (27%) of patients with RS. Time to RS according to the Kaplan-Meier analysis for rs4987852 is shown in Figure 1. This SNP is located in a region in which t(14;18) translocation breakpoints commonly occur in follicular lymphoma and overexpression of BCL2 leads to an increased incidence of B-cell lymphomas in mice. Conclusion Our results suggest that inherited genetic polymorphisms predispose CLL patients to develop RS. Specifically, SNP (rs4987852) present on the BCL2 gene on chromosome 18 in CLL is associated with an increased risk of transformation to RS. These observations require replication in other CLL cohorts. Disclosures: Shanafelt: Genentech: Research Funding; Glaxo-Smith-Kline: Research Funding; Cephalon: Research Funding; Hospira: Research Funding; Celgene: Research Funding; Polyphenon E International: Research Funding.

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Mutant p53 Gain of Function and Chemoresistance: The Role of Mutant p53 in Response to Clinical Chemotherapy

Chemotherapy ◽

10.1159/000446361 ◽

2016 ◽

Vol 62 (1) ◽

pp. 43-53 ◽

Cited By ~ 35

Author(s):

Chao He ◽

Lun Li ◽

Xuan Guan ◽

Li Xiong ◽

Xiongying Miao

Keyword(s):

B Cell Lymphoma ◽

Chemotherapeutic Agents ◽

Lymphocytic Leukemia ◽

Chemotherapy Response ◽

Mutant P53 ◽

Gain Of Function ◽

Pubmed Database ◽

Response To Chemotherapy ◽

The Impact

Purpose: To review mechanisms underlying mutant p53 (mutp53) gain of function (GOF) and mutp53-induced chemoresistance, and to investigate the role of mutp53 in response to clinical chemotherapy. Methods: We searched the PubMed database for clinical studies from the past decade, including data evaluating the impact of mutp53 in clinical chemotherapy response. Results: Interactions between mutp53 and transcriptional factors, proteins or DNA structures, as well as epigenetic regulation, contribute to mutp53 GOF. Major mechanisms of mutp53-induced chemoresistance include enhanced drug efflux and metabolism, promoting survival, inhibiting apoptosis, upregulating DNA repair, suppressing autophagy, elevating microenvironmental resistance and inducing a stem-like phenotype. Clinically, mutp53 predicted resistance to chemotherapy in diffuse large B-cell lymphoma, and esophageal and oropharyngeal cancers, but its impact on chronic lymphocytic leukemia was unclear. In bladder cancer, mutp53 did not predict resistance, whereas in some breast and ovarian cancers, it was associated with sensitivity to certain chemotherapeutic agents. Conclusion: mutp53 has an intricate role in the response to clinical chemotherapy and should not be interpreted in isolation. Furthermore, when predicting tumor response to chemotherapy based on the p53 status, the drugs used should also be taken into consideration. These concepts require further investigation.

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