scholarly journals Hotspot DNMT3A mutations in clonal hematopoiesis and acute myeloid leukemia sensitize cells to azacytidine via viral mimicry response

Nature Cancer ◽  
2021 ◽  
Vol 2 (5) ◽  
pp. 527-544 ◽  
Author(s):  
Marina Scheller ◽  
Anne Kathrin Ludwig ◽  
Stefanie Göllner ◽  
Christian Rohde ◽  
Stephen Krämer ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Clonal Hematopoiesis ◽  
Viral Mimicry ◽  
Acute Myeloid

scholarly journals Hotspot DNMT3A mutations in Clonal Hematopoiesis and Acute Myeloid Leukemia sensitize cells to Azacytidine via viral mimicry response

2021 ◽  
Author(s):  
Marina Scheller ◽  
Anne Kathrin Ludwig ◽  
Stefanie Göllner ◽  
Christian Rohde ◽  
Stephen Krämer ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Dna Methyltransferase ◽  
Predictive Marker ◽  
Protein Translation ◽  
Dna Hypomethylation ◽  
Hematopoietic Stem ◽  
Clonal Hematopoiesis ◽  
Viral Mimicry ◽  
Acute Myeloid

Abstract Somatic mutations in DNA Methyltransferase 3A (DNMT3A) are among the most frequent alterations in clonal hematopoiesis (CH) and Acute Myeloid Leukemia (AML), with a hotspot in exon 23 at arginine 882 (DNMT3A-R882). Here we demonstrate that DNMT3A-R882H-dependent CH- and AML cells are specifically susceptible to the hypomethylating agent azacytidine (AZA). Addition of AZA to chemotherapy prolonged AML survival solely in patients with DNMT3A-R882 mutation, suggesting its potential as a novel predictive marker for AZA response. AML and CH mouse models confirmed AZA susceptibility specifically in DNMT3A-R882H-expressing cells. Hematopoietic stem and progenitor cells expressing DNMT3A-R882H exhibited cell-autonomous viral mimicry response as a result of focal DNA hypomethylation at retrotransposon sequences. Administration of AZA boosted hypomethylation of retrotransposons specifically in DNMT3A-R882H expressing cells and maintained elevated levels of canonical interferon-stimulated genes (ISGs), thus leading to suppressed protein translation and increased apoptosis.

scholarly journals Erdheim–Chester Disease and Acute Myeloid Leukemia with Mutated NPM1 in a Patient with Clonal Hematopoiesis: A Case Report

2020 ◽  
Vol Volume 13 ◽  
pp. 11689-11695
Author(s):  
Sotirios G Papageorgiou ◽  
Aspasia Divane ◽  
Maria Roumelioti ◽  
Christine Kottaridi ◽  
Anthi Bouchla ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Case Report ◽  
Myeloid Leukemia ◽  
Clonal Hematopoiesis ◽  
Erdheim Chester Disease ◽  
Erdheim Chester ◽  
Chester Disease ◽  
Acute Myeloid

scholarly journals Clonal hematopoiesis and measurable residual disease assessment in acute myeloid leukemia

Blood ◽  
2020 ◽  
Vol 135 (20) ◽  
pp. 1729-1738 ◽  
Author(s):  
Robert P. Hasserjian ◽  
David P. Steensma ◽  
Timothy A. Graubert ◽  
Benjamin L. Ebert
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Residual Disease ◽  
Molecular Genetic ◽  
Disease Assessment ◽  
Clonal Hematopoiesis ◽  
Myeloid Neoplasm ◽  
Measurable Residual Disease ◽  
Acute Myeloid

Abstract Current objectives regarding treatment of acute myeloid leukemia (AML) include achieving complete remission (CR) by clinicopathological criteria followed by interrogation for the presence of minimal/measurable residual disease (MRD) by molecular genetic and/or flow cytometric techniques. Although advances in molecular genetic technologies have enabled highly sensitive detection of AML-associated mutations and translocations, determination of MRD is complicated by the fact that many treated patients have persistent clonal hematopoiesis (CH) that may not reflect residual AML. CH detected in AML patients in CR includes true residual or early recurrent AML, myelodysplastic syndrome or CH that is ancestral to the AML, and independent or newly emerging clones of uncertain leukemogenic potential. Although the presence of AML-related mutations has been shown to be a harbinger of relapse in multiple studies, the significance of other types of CH is less well understood. In patients who undergo allogeneic hematopoietic cell transplantation (HCT), post-HCT clones can be donor-derived and in some cases engender a new myeloid neoplasm that is clonally unrelated to the recipient’s original AML. In this article, we discuss the spectrum of CH that can be detected in treated AML patients, propose terminology to standardize nomenclature in this setting, and review clinical data and areas of uncertainty among the various types of posttreatment hematopoietic clones.

Clonal Hematopoiesis and risk of Acute Myeloid Leukemia

2019 ◽  
Vol 32 (2) ◽  
pp. 177-185 ◽  
Author(s):  
Pinkal Desai ◽  
Duane Hassane ◽  
Gail J. Roboz
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Clonal Hematopoiesis ◽  
Acute Myeloid

scholarly journals Clonal hematopoiesis and risk of acute myeloid leukemia

Haematologica ◽  
2019 ◽  
Vol 104 (12) ◽  
pp. 2410-2417 ◽  
Author(s):  
Andrew L. Young ◽  
R. Spencer Tong ◽  
Brenda M. Birmann ◽  
Todd E. Druley
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Clonal Hematopoiesis ◽  
Acute Myeloid

scholarly journals Gilteritinib induces differentiation in relapsed and refractory FLT3-mutated acute myeloid leukemia

2019 ◽  
Vol 3 (10) ◽  
pp. 1581-1585 ◽  
Author(s):  
Christine M. McMahon ◽  
Jonathan Canaani ◽  
Bryan Rea ◽  
Rachel L. Sargent ◽  
Julianne N. Qualtieri ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Genetic Evolution ◽  
Clonal Hematopoiesis ◽  
Key Points ◽  
Acute Myeloid

Key Points Gilteritinib induces 2 distinct marrow responses in FLT3-mutated AML: responses with and without differentiation. Ongoing clonal hematopoiesis is ubiquitous during gilteritinib therapy and may promote genetic evolution and drug resistance.

Post-remission clonal hematopoiesis; Practical implications for measurable residual disease assessment in acute myeloid leukemia (AML).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 7529-7529
Author(s):  
Sanam Loghavi ◽  
Tomoyuki Tanaka ◽  
Ken Furudate ◽  
Sa A Wang ◽  
Koichi Takahashi
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Disease Status ◽  
Leukemic Cells ◽  
Disease Assessment ◽  
Individual Gene ◽  
Clonal Hematopoiesis ◽  
Measurable Residual Disease ◽  
Acute Myeloid

7529 Background: Clonal Hematopoiesis may persist following complete remission (CR) in patients with acute myeloid leukemia (AML) but does not necessarily indicate residual AML and may represent persistence of pre-leukemic stem cells. Post-remission CH identified by NGS has not been systemically studied in parallel with measurable residual disease (MRD) detection by flow cytometric immunophenotyping (FCI). Methods: We studied bone marrow sample from AML patients at baseline and CR by targeted deep NGS of 295 genes (median 403x depth) and compared the results to FCI. Measurable residual disease (MRD) detection by FCI was performed by comparing the phenotype at CR to baseline and by detection of leukemia associated immunophenotype (LAIP) and derivation from normal (DFN) (sensitivity: 0.1%). Post-CR CH was defined as presence of mutations originally detected in AML with variant allele frequency > 2.5%. FCI results were categorized into 4 groups: a) AML MRD negative by LAIP or DFN b) AML MRD+ (similar to baseline) c) AML MRD+ (different from baseline), d) Negative for AML MRD, but aberrant phenotype suggestive of pre-leukemic cells. We correlated FCI and NGS results. Results: 101 patients were included in the study. 45 (45%) had persistent post-CR clonal hematopoiesis; 23 (51%) had phenotypic alterations detected by FCI including AML MRD+ in 18 (40%) and pre-leukemic cells in 5 (10%). Among patient with no detectable mutations by NGS (n = 56; 55%), 14 (25%) had FCI aberrancies including AML MRD+ in 4 (7%) and pre-leukemic cells in 10 (18%). CH was significantly more common in samples with residual phenotypic aberrancies detected by FCI (p = 0.004). There was no significant correlation between FCI group d and persistent CH (p = 0.4). Persistent ASXL1 (p = 0.024, OR = 7.2 ) and RUNX1 (p = 0.016; OR = 17.3) mutations were significantly associated with FCI abnormalities. The correlation coefficient between FCI abnormalities and RUNX1 mutations inferred from a Bayesian network structure was 0.66. Conclusions: NGS and FCI are complementary in evaluating post treatment disease status in AML. Post CR-CH is associated with phenotypic abnormalities that either represent residual AML or pre-leukemic cells. The latter may not have the same prognostic implications as AML MRD; however, the association with outcome needs to be elucidated. Single cell DNA sequencing technologies may be helpful in more accurately deciphering the association of individual gene mutations and their contribution to phenotypic aberrations.

Clonal Dynamics and clinical implications of Post-Remission Clonal Hematopoiesis in Acute Myeloid Leukemia (AML)

Blood ◽  
2021 ◽  
Author(s):  
Tomoyuki Tanaka ◽  
Kiyomi Morita ◽  
Feng Wang ◽  
Sanam Loghavi ◽  
Ken Furudate ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Stem Cell Transplant ◽  
Clinical Implications ◽  
Atherosclerotic Cardiovascular Disease ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Clonal Hematopoiesis ◽  
Acute Myeloid

While clonal hematopoiesis (CH) can precede the development of acute myeloid leukemia (AML), it can also persist after achieving remission. Long-term clonal dynamics and clinical implications of persistent CH are not well understood. Here, we studied the prevalence, dynamics and clinical implications of post-remission CH in 164 AML patients who attained complete remission after induction chemotherapies. Post-remission CH was identified in 79 (49%) patients. Post-remission CH persisted long-term in 91% of the trackable patients despite treatment with various types of consolidation and maintenance therapies. Post-remission CH was eradicated in 20 out of 21 (95%) patients who underwent allogeneic stem cell transplant. While patients with post-remission CH as a group had comparable hematopoiesis with those without it, patients with persistent TET2 mutations showed significant neutropenia long-term. Post-remission CH had little impact on relapse risk, non-relapse mortality, and incidence of atherosclerotic cardiovascular disease, although the clinical impact of post-CR CH was heterogeneous among different mutations. These data suggest that while residual clonal hematopoietic stem cells (HSCs) are generally resistant to consolidation and maintenance therapies, they retain the ability to maintain normal hematopoiesis and have little impact on clinical outcomes, although larger study is needed to dissect the gene-specific heterogeneity.

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