BRCA1/BRCA2-containing complex 3 (BRCC3) is a Lysine 63-specific deubiquitinating enzyme (DUB) involved in inflammasome activity, interferon signaling, and DNA damage repair. Recurrent mutations in ...BRCC3 have been reported in myelodysplastic syndromes (MDS) but not in de novo AML. In one of our recent studies, we found BRCC3 mutations selectively in 9/191 (4.7%) cases with t(8;21)(q22;q22.1) AML but not in 160 cases of inv(16)(p13.1q22) AML. Clinically, AML patients with BRCC3 mutations had an excellent outcome with an event-free survival of 100%. Inactivation of BRCC3 by CRISPR/Cas9 resulted in improved proliferation in t(8;21)(q22;q22.1) positive AML cell lines and together with expression of AML1-ETO induced unlimited self-renewal in mouse hematopoietic progenitor cells in vitro. Mutations in BRCC3 abrogated its deubiquitinating activity on IFNAR1 resulting in an impaired interferon response and led to diminished inflammasome activity. In addition, BRCC3 inactivation increased release of several cytokines including G-CSF which enhanced proliferation of AML cell lines with t(8;21)(q22;q22.1). Cell lines and primary mouse cells with inactivation of BRCC3 had a higher sensitivity to doxorubicin due to an impaired DNA damage response providing a possible explanation for the favorable outcome of BRCC3 mutated AML patients.
Several molecular aberrations affect the prognosis of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with excess blasts (EB). This study aimed to determine the ...incidence and clinical impact of molecular genetic aberrations in Thai patients with AML and MDS-EB, detected by the next-generation sequencing (NGS) technique. This prospective, observational study was conducted between 2018 and 2020 on newly diagnosed Thai AML or MDS-EB patients aged above 15 years. NGS was performed using a custom amplicon-based targeted enrichment assay for 42 genes recurrently mutated in myeloid neoplasms. The molecular results were correlated with baseline patient and disease characteristics as well as outcomes. Forty-nine patients were enrolled in this study. The median age was 56 years (interquartile range IQR, 44–64), with nearly equal proportions of males and females. The median number of mutations was 3 (IQR, 2–4). The most frequent alterations were
FLT3
internal tandem duplications (ITD) (28.6%),
DNMT3A
(24.5%), and
WT1
(22.4%) mutations.
FLT3
-ITD was more frequent in the de novo AML group than in the MDS/secondary AML group, whereas in the MDS/secondary AML group,
ASXL1
,
ETV6,
and
SRSF2
mutations were more frequent. Patients aged greater than 65 years and patients with mutated
TP53
were more likely to have inferior overall survival from multivariate analysis.
FLT3
-ITD was the most common mutation among newly diagnosed Thai AML patients.
TP53
mutation and advanced age were independent adverse factors for survival outcome. The genetic landscapes of AML patients vary between national populations. Thai Clinical Trials Registry identifier: TCTR20190227003.
Acute promyelocytic leukemia, a subtype of acute myeloid leukemia, is highly curable. In subgroup of patients with non-high-risk acute promyelocytic leukemia, intravenous arsenic trioxide plus ...all-trans-retinoic acid is considered the preferred regimen for acute promyelocytic leukemia. Recently, there are interests in the use of the oral form of arsenic, named the Realgar-Indigo naturalis formula, but the data on its efficacy and safety are still relatively limited. The current study was conducted with the aims to identify and summarize the results of all available randomized-controlled studies. A systematic review was conducted in the 2 major databases, utilizing the terms for arsenic and acute promyelocytic leukemia. Eligible studies had to be randomized-controlled studies that compared efficacy and/or adverse effects of oral arsenic versus intravenous arsenic for treatment of patients with acute promyelocytic leukemia. The Mantel-Haenszel method was used to pool the effect estimates and 95% confidence intervals of the included studies together. A total of 4 randomized controlled studies with 482 patients with acute promyelocytic leukemia (258 in Realgar-Indigo naturalis formula group and 224 in intravenous arsenic trioxide group) were included in the meta-analysis. The chances of achieving complete remission were numerically higher in the Realgar-Indigo naturalis formula group but the difference was not statistically significant (pooled odds ratio: 4.59, 95% CI: 0.74-28.57, I
2 = 0%). Similarly, other efficacy outcomes, including 30-day mortality rate, overall survival, and event-free survival, also tended to favor the Realgar-Indigo naturalis formula group but the difference was not statistically significant. There was no significant difference in the chance of developing differentiation syndrome, cardiac complications, grades 3 to 4 liver toxicity, grades 3 to 4 renal toxicity, and infection between the 2 groups. The results may suggest that all-trans-retinoic acid plus oral Realgar-Indigo naturalis formula regimen is, at minimum, not a worse alternative to the standard all-trans-retinoic acid plus intravenous intravenous arsenic trioxide regimen for treatment of acute promyelocytic leukemia, especially for patients with low-to-intermediate risk.
We have conducted the first study to determine the diagnostic potential of the CD14++CD16+ intermediate monocytes as compared to the pro-angiogenic subset of CD14++CD16+TIE2+ TIE2-expressing ...monocytes (TEMs) in cancer. These monocyte populations were investigated by flow cytometry in healthy volunteers (N = 32) and in colorectal carcinoma patients with localized (N = 24) or metastatic (N = 37) disease. We further determined blood levels of cytokines associated with monocyte regulation. The results revealed the intermediate monocyte subset to be significantly elevated in colorectal cancer patients and to show the highest frequencies in localized disease. Multivariate regression analysis identified intermediate monocytes as a significant independent variable in cancer prediction. With a cut-off value at 0.37% (intermediate monocytes of total leukocytes) the diagnostic sensitivity and specificity ranged at 69% and 81%, respectively. In contrast, TEM levels were elevated in localized cancer but did not differ significantly between groups and none of the cytokines correlated with monocyte subpopulations. Of interest, in vitro analyses supported the observation that intermediate monocytes were more potently induced by primary as opposed to metastatic cancer cells which may relate to the immunosuppressive milieu established in the advanced stage of metastatic disease. In conclusion, intermediate monocytes as compared to TIE2-expressing monocytes are a more sensitive diagnostic indicator of colorectal cancer.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Aging is associated with increased mutational burden in every tissue studied. Occasionally, fitness-increasing mutations will arise, leading to stem cell clonal expansion. This process occurs in ...several tissues but has been best studied in blood. Clonal hematopoiesis is associated with an increased risk of blood cancers, such as acute myeloid leukemia, which result if additional cooperating mutations occur. Surprisingly, it is also associated with an increased risk of nonmalignant diseases, such as atherosclerotic cardiovascular disease. This may be due to enhanced inflammation in mutated innate immune cells, which could be targeted clinically with anti-inflammatory drugs. Recent studies have uncovered other factors that predict poor outcomes in patients with clonal hematopoiesis, such as size of the mutant clone, mutated driver genes, and epigenetic aging. Though clonality is inevitable and largely a function of time, recent work has shown that inherited genetic variation can also influence this process. Clonal hematopoiesis provides a paradigm for understanding how age-related changes in tissue stem cell composition and function influence human health.
Patients with acute myeloid leukemia (AML) harboring FLT3 internal tandem duplications (ITDs) have poor outcomes, in particular AML with a high (≥0.5) mutant/wild-type allelic ratio (AR). The 2017 ...European LeukemiaNet (ELN) recommendations defined 4 distinct FLT3-ITD genotypes based on the ITD AR and the NPM1 mutational status. In this retrospective exploratory study, we investigated the prognostic and predictive impact of the NPM1/FLT3-ITD genotypes categorized according to the 2017 ELN risk groups in patients randomized within the RATIFY trial, which evaluated the addition of midostaurin to standard chemotherapy. The 4 NPM1/FLT3-ITD genotypes differed significantly with regard to clinical and concurrent genetic features. Complete ELN risk categorization could be done in 318 of 549 trial patients with FLT3-ITD AML. Significant factors for response after 1 or 2 induction cycles were ELN risk group and white blood cell (WBC) counts; treatment with midostaurin had no influence. Overall survival (OS) differed significantly among ELN risk groups, with estimated 5-year OS probabilities of 0.63, 0.43, and 0.33 for favorable-, intermediate-, and adverse-risk groups, respectively (P < .001). A multivariate Cox model for OS using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable revealed treatment with midostaurin, allogeneic HCT, ELN favorable-risk group, and lower WBC counts as significant favorable factors. In this model, there was a consistent beneficial effect of midostaurin across ELN risk groups.
•OS of patients with FLT3-ITD differs significantly when categorized by the 2017 ELN risk stratification.•In a multivariate Cox model for OS, there is a consistent beneficial effect of midostaurin across the 3 2017 ELN risk groups.
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In the international randomized phase 3 RATIFY (Randomized AML Trial In FLT3 in patients less than 60 Years old) trial, the multikinase inhibitor midostaurin significantly improved overall and ...event-free survival in patients 18 to 59 years of age with FLT3-mutated acute myeloid leukemia (AML). However, only 59% of patients in the midostaurin arm achieved protocol-specified complete remission (CR), and almost half of patients achieving CR relapsed. To explore underlying mechanisms of resistance, we studied patterns of clonal evolution in patients with FLT3-internal tandem duplications (ITD)-positive AML who were entered in the RATIFY or German-Austrian Acute Myeloid Leukemia Study Group 16-10 trial and received treatment with midostaurin. To this end, paired samples from 54 patients obtained at time of diagnosis and at time of either relapsed or refractory disease were analyzed using conventional Genescan-based testing for FLT3-ITD and whole exome sequencing. At the time of disease resistance or progression, almost half of the patients (46%) became FLT3-ITD negative but acquired mutations in signaling pathways (eg, MAPK), thereby providing a new proliferative advantage. In cases with FLT3-ITD persistence, the selection of resistant ITD clones was found in 11% as potential drivers of disease. In 32% of cases, no FLT3-ITD mutational change was observed, suggesting either resistance mechanisms bypassing FLT3 inhibition or loss of midostaurin inhibitory activity because of inadequate drug levels. In summary, our study provides novel insights into the clonal evolution and resistance mechanisms of FLT3-ITD–mutated AML under treatment with midostaurin in combination with intensive chemotherapy.
•At the time of disease resistance or progression, ∼50% of patients treated with midostaurin become FLT3-ITD negative.•FLT3-ITD persistence can be caused by selection of resistant FLT3 clones, mechanisms bypassing FLT3 inhibition, or insufficient drug activity.
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