Molecular dissection of a hyper-aggressive CBFB-MYH11/FLT3-ITD-positive acute myeloid leukemia.
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ABSTRACT:
SUBMITTER: Lo Iudice G
PROVIDER: S-EPMC9258203 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:A 77 year-old female was found with FAB M4Eo acute myeloid leukemia. Although CBFB-MYH11 mRNA was detected in RT-PCR, the conventional cytogenetic analysis failed to reveal inv(16). Fluorescence in situ hybridization (FISH) and the sequence analysis revealed a fusion between the exon 5 of CBFB and the exon 8 of MYH11, resulting in a minor variant fusion product previously reported as type D. In order to detect the cryptic inv(16) type D, both FISH and RT-PCR are required, and furthermore, the primers for the sequence analysis needs to be selected for the proper diagnosis.
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Project description:Acute myeloid leukemia (AML) is an aggressive hematologic malignancy which is cured in a minority of patients. A FLT3-internal tandem duplication (ITD) mutation, found in approximately a quarter of patients with de novo AML, imparts a particularly poor prognosis. Patients with FLT3-ITD AML often present with more aggressive disease and have a significantly higher propensity for relapse after remission. The therapeutic approach for these patients has traditionally included intensive induction chemotherapy, followed by consolidative chemotherapy or hematopoietic cell transplantation (HCT). In recent years, multiple small molecule inhibitors of the FLT3 tyrosine kinase have been studied preclinically and in clinical trials. The earlier generation of these agents, often non-specific and impacting a variety of tyrosine kinases, produced at best transient peripheral blood responses in early clinical trials. Additionally, the combination of FLT3 inhibitors with cytotoxic regimens has not, as of yet, demonstrated an improvement in overall survival. Nevertheless, multiple current trials, including those with sorafenib, lestaurtinib, and midostaurin, continue to study the combination of FLT3 inhibitors with standard chemotherapy. Factors such as sustained FLT3 inhibition, protein binding, pharmacokinetics, and the presence of elevated FLT3-ligand levels appear to significantly impact the potency of these agents in vivo. In recent years, the development of more specific and potent agents has generated hope that FLT3 inhibitors may play a more prominent role in the treatment of FLT3-ITD AML in the near future. Nevertheless, questions remain regarding the optimal timing and schedule for incorporation of FLT3 inhibitors. The suitability, type, and timing of allogeneic HCT in the therapeutic approach for these patients are also issues which require further study and definition. Recent retrospective data appears to support the efficacy of allogeneic HCT in first complete remission, possibly due to a graft versus leukemia effect. However, larger prospective studies are necessary to further elucidate the role of HCT and its potential combination with FLT3 inhibitor therapy. We are hopeful that current clinical investigation will lead to an optimization and improvement of outcomes for these patients.
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Project description:Aberrant cytokine signaling initiated from mutant receptor tyrosine kinases (RTKs) provides critical growth and survival signals in high risk acute myeloid leukemia (AML). Inhibitors to FLT3 have already been tested in clinical trials, however, drug resistance limits clinical efficacy. Mutant receptor tyrosine kinases are mislocalized in the endoplasmic reticulum (ER) of AML and play an important role in the non-canonical activation of signal transducer and activator of transcription 5 (STAT5). Here, we have tested a potent new drug called imipramine blue (IB), which is a chimeric molecule with a dual mechanism of action. At 200-300?nM concentrations, IB is a potent inhibitor of STAT5 through liberation of endogenous phosphatase activity following NADPH oxidase (NOX) inhibition. However, at 75-150?nM concentrations, IB was highly effective at killing mutant FLT3-driven AML cells through a similar mechanism as thapsigargin (TG), involving increased cytosolic calcium. IB also potently inhibited survival of primary human FLT3/ITD+ AML cells compared to FLT3/ITDneg cells and spared normal umbilical cord blood cells. Therefore, IB functions through a mechanism involving vulnerability to dysregulated calcium metabolism and the combination of fusing a lipophilic amine to a NOX inhibiting dye shows promise for further pre-clinical development for targeting high risk AML.
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Project description:MiR-126 and miR-155 are key microRNAs (miRNAs) that regulate, respectively, hematopoietic cell quiescence and proliferation. Herein we showed that in acute myeloid leukemia (AML), the biogenesis of these two miRNAs is interconnected through a network of regulatory loops driven by the FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD). In fact, FLT3-ITD induces the expression of miR-155 through a noncanonical mechanism of miRNA biogenesis that implicates cytoplasmic Drosha ribonuclease III (DROSHA). In turn, miR-155 down-regulates SH2-containing inositol phosphatase 1 (SHIP1), thereby increasing phosphor-protein kinase B (AKT) that in turn serine-phosphorylates, stabilizes, and activates Sprouty related EVH1 domain containing 1 (SPRED1). Activated SPRED1 inhibits the RAN/XPO5 complex and blocks the nucleus-to-cytoplasm transport of pre-miR-126, which cannot then complete the last steps of biogenesis. The net result is aberrantly low levels of mature miR-126 that allow quiescent leukemia blasts to be recruited into the cell cycle and proliferate. Thus, miR-126 down-regulation in proliferating AML blasts is downstream of FLT3-ITD–dependent miR-155 expression that initiates a complex circuit of concatenated regulatory feedback (i.e., miR-126/SPRED1, miR-155/human dead-box protein 3 [DDX3X]) and feed-forward (i.e., miR-155/SHIP1/AKT/miR-126) regulatory loops that eventually converge into an output signal for leukemic growth.
| S-EPMC9169767 | biostudies-literature
Project description:Inversion of chromosome 16 (inv(16)) generates a fusion gene CBFB-MYH11, which is a driver mutation for acute myeloid leukemia (AML). Gene expression profiling suggests that Gata2, a hematopoietic transcription factor, is a top upregulated gene in preleukemic Cbfb-MYH11 knockin mice and is expressed in human inv(16) AML. On the other hand, we have also identified recurrent monoallelic deletions of GATA2 in relapsed human CBF-AML patients. To clarify the role of Gata2 in leukemogenesis by Cbfb-MYH11, we generated conditional Cbfb-MYH11 knockin mice with Gata2 heterozygous knockout. Gata2 heterozygous knockout reduced abnormal myeloid progenitors, which are capable of inducing leukemia in the Cbfb-MYH11 mice. Consequently, Cbfb-MYH11 mice with Gata2 heterozygous knockout developed leukemia with longer latencies than those with intact Gata2. Interestingly, leukemic cells with Gata2 heterozygous knockout gained higher number of mutations and showed more aggressive phenotype in both primary and transplanted mice. Moreover, leukemic cells with Gata2 heterozygous knockout showed higher repopulating capacity in competitive transplantation experiments. In summary, reduction of Gata2 activity affects mutational dynamics of leukemia with delayed leukemia onset in Cbfb-MYH11 knockin mice, but paradoxically results in a more aggressive leukemia phenotype, which may be correlated with leukemia relapse or poor prognosis in human patients.
| S-EPMC7056539 | biostudies-literature
Project description:FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) is one of the most common somatic mutations in acute myeloid leukemia (AML). However, the molecular structure characteristics and widely accepted prognostic factors for FLT3-ITD are still not well described. This study aimed to retrospectively examine 81 patients with FLT3-ITD-positive AML diagnosed and treated at the First Affiliated Hospital of Zhejiang University from December 2013 to March 2018 using the next-generation sequencing 185-gene platform. High variant allele frequency (VAF) [> 0.48, P = 0.0089 for overall survival (OS), P = 0.13 for relapse-free survival (RFS)], multiple ITDs (> 1 ITDs, P = 0.011 for OS, P = 0.033 for RFS) and longer insertion length (> 69 bp, P = 0.14 for OS, P = 0.0078 for RFS) predicted poor survival. The study further proposed an easily applicable scoring model for OS using the Least Absolute Shrinkage and Selector Operation (LASSO) Cox regression model. Also, an independent cohort of 30 patients was used for external model validation. The mode was expressed as follows: 0.659 × FLT3-ITD VAF + 0.375 × FLT3-ITD number + 0.807 × Age + 0.688 × DNMT3A + 1.939 × U2AF1 (FLT3-ITD VAF > 0.48 scored 1; FLT3-ITD number scored 1 if carried 1 ITD, 2 if carried ≥ 2 ITDs; age > 44 years scored 1, the presence of DNMT3A or U2AF1 scored 1; 0 for other conditions). It categorized patients into low-risk (L-R, score < 1, n = 20) and high-risk (H-R, score ≥ 1, n = 61) groups based on the risk score with a significant difference in survival (3-year OS, P < 0.0001; 3-year RFS, P = 0.0005). A prognostic nomogram that integrated these five factors was developed with a concordance index calculation [OS: 0.68, 95% CI (0.64-0.72)].
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Project description:FLT3 kinase internal tandem duplication (ITD) mutations are common in acute myeloid leukemia (AML) and are associated with poor clinical outcomes. Although initial responses to FLT3 tyrosine kinase inhibitors (TKIs) are observed in FLT3-ITD-positive patients, subsequent relapse often occurs upon acquisition of secondary FLT3 kinase domain (KD) mutations, primarily at residues D835 and F691. Using biochemical assays, we determined that crenolanib, a novel TKI, demonstrates type I properties and is active against FLT3 containing ITD and/or D835- or F691-activating mutations. Potent activity was observed in FLT3-ITD-positive AML cell lines. Crenolanib delayed the outgrowth of MV4-11 cells in a xenograft mouse model, whereas in combination with the type II TKI sorafenib, a significant decrease in leukemic burden (P < .001) and prolonged survival (P < .01) was observed compared with either type I or II TKI alone. Crenolanib was active against Ba/F3 cells harboring FLT3-ITD and secondary KD mutations and sorafenib-resistant MOLM-13 cells containing FLT3-ITD/D835Y both in vitro and in vivo. In addition, crenolanib inhibited drug-resistant AML primary blasts with FLT3-ITD and D835H/Y mutations. These preclinical data demonstrate that crenolanib is effective against FLT3-ITD containing secondary KD mutations, suggesting that crenolanib may be a useful therapeutic agent for TKI-naive and drug-resistant FLT3-ITD-positive AML.
| S-EPMC3837509 | biostudies-literature
Project description:Proteins created from recurrent fusion genes like CBFB-MYH11 are prevalent in acute myeloid leukemia (AML), often necessary for leukemogenesis, persistent throughout the disease course, and highly leukemia specific, making them attractive neoantigen targets for immunotherapy. A nonameric peptide derived from a prevalent CBFB-MYH11 fusion protein was found to be immunogenic in HLA-B*40:01+ donors. High-avidity CD8+ T cell clones isolated from healthy donors killed CBFB-MYH11+ HLA-B*40:01+ AML cell lines and primary human AML samples in vitro. CBFB-MYH11-specific T cells also controlled CBFB-MYH11+ HLA-B*40:01+ AML in vivo in a patient-derived murine xenograft model. High-avidity CBFB-MYH11 epitope-specific T cell receptors (TCRs) transduced into CD8+ T cells conferred antileukemic activity in vitro. Our data indicate that the CBFB-MYH11 fusion neoantigen is naturally presented on AML blasts and enables T cell recognition and killing of AML. We provide proof of principle for immunologically targeting AML-initiating fusions and demonstrate that targeting neoantigens has clinical relevance even in low-mutational frequency cancers like fusion-driven AML. This work also represents a first critical step toward the development of TCR T cell immunotherapy targeting fusion gene-driven AML.
| S-EPMC7524498 | biostudies-literature
Project description:Acute myeloid leukemia subtype M4 with eosinophilia is associated with a chromosome 16 inversion that creates a fusion gene CBFB-MYH11. We have previously shown that CBFB-MYH11 is necessary but not sufficient for leukemogenesis. Here, we report the identification of genes that specifically cooperate with CBFB-MYH11 in leukemogenesis. Neonatal injection of Cbfb-MYH11 knock-in chimeric mice with retrovirus 4070A led to the development of acute myeloid leukemia in 2-5 months. Each leukemia sample contained one or a few viral insertions, suggesting that alteration of one gene could be sufficient to synergize with Cbfb-MYH11. The chromosomal position of 67 independent retroviral insertion sites (RISs) was determined, and 90% of the RISs mapped within 10 kb of a flanking gene. In total, 54 candidate genes were identified; six of them were common insertion sites (CISs). CIS genes included members of a zinc finger transcription factors family, Plag1 and Plagl2, with eight and two independent insertions, respectively. CIS genes also included Runx2, Myb, H2T24, and D6Mm5e. Comparison of the remaining 48 genes with single insertion sites with known leukemia-associated RISs indicated that 18 coincide with known RISs. To our knowledge, this retroviral genetic screen is the first to identify genes that cooperate with a fusion gene important for human myeloid leukemia.
| S-EPMC387350 | biostudies-literature