Clinical and molecular profiling of AML patients with chromosome 7 or 7q deletions in the context of<i>TP53</i>alterations and venetoclax treatment

Abbas, Hussein A.; Ayoub, Edward; Sun, Hanxiao; Kanagal‐Shamanna, Rashmi; Short, Nicholas J.; Issa, Ghayas C.; Yılmaz, Musa; Pierce, Sherry; Rivera, Daniel; Cham, Brent; Wing, Shane; Li, Ziyi; Hammond, Danielle; Jabbour, Elias; Borthakur, Gautam; Andreeff, Michael; Daver, Naval; Kadia, Tapan M.; Konopleva, Marina; DiNardo, Courtney D.; Ravandi, Farhad

doi:10.1080/10428194.2022.2118533

Cited by 6 publications

(5 citation statements)

References 22 publications

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“…7A ). Given that AML patients with monocytic differentiation and del7/7q are reported to have resistance to venetoclax-based therapy 10 , 53 , we evaluated the correlation of IFNγ signaling score with drug sensitivity. We found a strong positive correlation between IFNγ signaling score and venetoclax resistance, indicating that IFNγ signaling confers venetoclax resistance (Fig.…”

Section: Resultsmentioning

confidence: 99%

Comprehensive characterization of IFNγ signaling in acute myeloid leukemia reveals prognostic and therapeutic strategies

Wang,

Reville,

Yassouf

et al. 2024

Nat Commun

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Interferon gamma (IFNγ) is a critical cytokine known for its diverse roles in immune regulation, inflammation, and tumor surveillance. However, while IFNγ levels were elevated in sera of most newly diagnosed acute myeloid leukemia (AML) patients, its complex interplay in AML remains insufficiently understood. We aim to characterize these complex interactions through comprehensive bulk and single-cell approaches in bone marrow of newly diagnosed AML patients. We identify monocytic AML as having a unique microenvironment characterized by IFNγ producing T and NK cells, high IFNγ signaling, and immunosuppressive features. IFNγ signaling score strongly correlates with venetoclax resistance in primary AML patient cells. Additionally, IFNγ treatment of primary AML patient cells increased venetoclax resistance. Lastly, a parsimonious 47-gene IFNγ score demonstrates robust prognostic value. In summary, our findings suggest that inhibiting IFNγ is a potential treatment strategy to overcoming venetoclax resistance and immune evasion in AML patients.

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Section: Resultsmentioning

confidence: 99%

Comprehensive characterization of IFNγ signaling in acute myeloid leukemia reveals prognostic and therapeutic strategies

Wang,

Reville,

Yassouf

et al. 2024

Nat Commun

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“…59,60 Chromosome 7 aberrations frequently co-occur with TP53 Mu , À5/del(5q), and CK. 59 In AML, MDS, and CMML, À7 is more prevalent than del(7q). 61 While loss of the entirety of chromosome 60,65 In a large cohort study, isolated trisomy 8 MDS has a mOS of 22 months, but doubles to 44 months when associated with one additional CA.…”

Section: Chromosome 7 Abnormalitiesmentioning

confidence: 99%

“…Monosomy 7 (−7) and del(7q) are among the most frequently observed karyotypic abnormalities in myeloid disorders (12%–30% of de novo AML and 21% of MDS with cytogenetic abnormalities) 59,60 . Chromosome 7 aberrations frequently co‐occur with TP53 Mu , −5/del(5q), and CK 59 . In AML, MDS, and CMML, −7 is more prevalent than del(7q) 61 .…”

Section: Introductionmentioning

confidence: 99%

Molecular findings in myeloid neoplasms

TRAN

Siddon

2023

Int J Lab Hematology

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The proliferation of new molecular technologies in recent years has greatly advanced our knowledge of the genetics that underlie hematologic cancers. Particularly, with the advent and wide-implementation of next-generation sequencing (NGS), a host of somatic (and some germline) gene mutations have been identified as significant in the classification, prognostication, and treatment of the spectrum of myeloid neoplasms. These driver and disease modifier mutations now play a prominent role in the updated international diagnostic guidelines of acute myeloid leukemia (AML), myelodysplastic syndromes/neoplasms (MDS), and myeloproliferative neoplasms (MPN).As high-throughput technologies such as NGS increasingly become standard in the genetic evaluation of myeloid disorders, it is critical that clinicians understand the clinical relevance of these mutations in order to further personalize patient care. In this review we discuss some of the most essential somatic and cytogenetic findings.

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“… 92 Deletions in chromosome 7 (−7) or its long arm (7q − ) represent the most frequent adverse cytogenetic events in AML; T P53 and −5/5q are the most frequent co-occurring mutations and cytogenetic abnormalities in this AML subset. 93 …”

Section: Tp53-mutated Mds and Amlmentioning

confidence: 99%

“…92 Deletions in chromosome 7 (-7) or its long arm (7q -) represent the most frequent adverse cytogenetic events in AML; TP53 and -5/5q are the most frequent co-occurring mutations and cytogenetic abnormalities in this AML subset. 93 TP53 aberrations in AML include gene mutations, mostly involving the DNA binding domain of the gene, and deletions of different sizes implying the TP53 locus at the level of chromosome 17p13. Functional studies on missense TP53 mutant variants commonly observed in AML indicate loss-of-function effects and induction of effects comparable to those observed with complete TP53 inactivation; these findings have suggested a dominant negative effect as the primary force of selection of TP53 mutations in myeloid malignancies.…”

Section: Tp53-mutated Mds and Amlmentioning

confidence: 99%

Tp53-Mutated Myelodysplasia and Acute Myeloid Leukemia

Testa¹,

Castelli

Pelosi

2023

Mediterr J Hematol Infect Dis

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TP53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) form a distinct and heterogeneous group of myeloid malignancies associated with poor outcomes. Studies carried out in the last years have in part elucidated the complex role played by TP53 mutations in the pathogenesis of these myeloid disorders and in the mechanisms of drug resistance. A consistent number of studies has shown that some molecular parameters, such as the presence of a single or multiple TP53 mutations, the presence of concomitant TP53 deletions, the association with co-occurring mutations, the clonal size of TP53 mutations, the involvement of a single (monoallelic) or of both TP53 alleles (biallelic) and the cytogenetic architecture of concomitant chromosome abnormalities are major determinants of outcomes of patients. The limited response of these patients to standard treatments, including induction chemotherapy, hypomethylating agents, and venetoclax-based therapies and the discovery of an immune dysregulation have induced a shift to new emerging therapies, some of which being associated with promising efficacy. The main aim of these novel immune and nonimmune strategies consists in improving survival and in increasing the number of TP53-mutated MDS/AML patients in remission amenable to allogeneic stem cell transplantation. Keywords: myelodysplastic syndromes; acute myeloid leukemias; TP53; molecular abnormalities; gene sequencing; cytogenetic characterization

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Clinical and molecular profiling of AML patients with chromosome 7 or 7q deletions in the context ofTP53alterations and venetoclax treatment

Cited by 6 publications

References 22 publications

Comprehensive characterization of IFNγ signaling in acute myeloid leukemia reveals prognostic and therapeutic strategies

Comprehensive characterization of IFNγ signaling in acute myeloid leukemia reveals prognostic and therapeutic strategies

Molecular findings in myeloid neoplasms

Tp53-Mutated Myelodysplasia and Acute Myeloid Leukemia

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