RUNX1-RUNX1T1 fusion

Two patients died from infection following transplantation. Afatinib plus allo-HSCT may be an effective and safe new treatment strategy for RUNX1-RUNX1T1 positive AML patients with KIT-D816 mutation.

Dietary lipid deprivation or loss of the fatty acid transporter FATP3 by targeted deletion using CRISPR/Cas9 partially restored differentiation. These findings reveal the unique metabolic profile of pre-leukemic cells and propose FATP3 as a potential target for disrupting leukemogenesis.

RUNX1::RUNX1T1 expression in Mga-deficient murine hematopoietic cells leads to a more aggressive AML with a significantly shortened latency. These data show that MGA regulates multiple pro-proliferative pathways in hematopoietic cells and cooperates with the RUNX1::RUNX1T1 fusion oncoprotein to enhance leukemogenesis.

P3, N=204, Completed, University of Ulm | Active, not recruiting --> Completed

P=N/A, N=400, Completed, Acute Leukemia French Association | Recruiting --> Completed

2 patients did not achieve continuous RUNX1: : RUNX1T1 negative after preemptive therapy with Decitabine (DAC) and donor lymph infusion (DLI), and then was treated with Avapritinib, one's RUNX1: : RUNX1T1 fusion achieved continuously negative after 1 month treatment of Avapritinib, the other's achieved continuous negative after 7 months treatment of Avapritinib. Avapritinib is safe and effective in the prophylactic and preemptive treatment of AML with KIT mutation after allo-HSCT in children, which provides a clinical drug for the prevention of relapse after transplantation.

Protocol guidelines recommended immediate start of the first chemotherapy course (starting with etoposide [ETO] monotherapy for 5 days at 150 mg/m2 once daily) followed randomized by either cytarabine/mitoxantrone (MEC) or cytarabine/daunoxome or daunorubicin (D[x]EC). The NOPHO-DBH AML 2012 protocol is very effective in pediatric AML. The first chemotherapy course starts with five consecutive days of ETO monotherapy. We made use of this "ETO-window" in the management of HL patients, omitting invasive methods to reduce high WBCs.

In 11/13 patients, the mast cell fraction was positive for the CBF fusion but all other sorted cell fractions tested were negative. In the remaining two specimens, all cell fractions were negative, likely due to FISH sensitivity compared to RT-PCR. Both CBF fusions exhibited the same pattern, with fusions detected only in the mast cell fractions (7 RUNX1::RUNX1T1 and 4 CBFB::MYH11).

Both primary hematopoietic cells and the t(8;21) positive AML cell line SKNO-1 showed increased sensitivity to the GLI inhibitor GANT61 when expressing CSF3R T618I. Our findings suggest that during leukemogenesis, the RUNX1-RUNXT1 fusion and CSF3R mutation act in a synergistic manner to alter hedgehog signaling, which can be exploited therapeutically.

Demonstrating the feasibility of RUNX1-RUNX1T1 disruption, these findings were substantiated in isolated primary cells from a patient diagnosed with AML t(8;21). In conclusion, we demonstrate proof-of-principle of a dual intron-targeting CRISPR-Cas9 treatment strategy in AML t(8;21) without need for precise knowledge of the breakpoint location.

EVI-1 expression could be a helpful diagnostic, prognostic, and predictive biomarker for acute leukemia especially in AML.

Each resulted in RUNX1::RUNX1T1 fusion. Our findings demonstrate the importance of recognizing variant forms of t(8;21) translocations and emphasize the value of applying RUNX1::RUNX1T1 FISH for the detection of cryptic and complex rearrangements when abnormalities involving chromosome band 8q22 are observed in patients with AML.

Our study is the first to report the clinical impact of c-KIT and CEBPA mutations in pediatric patients with non-M3 CBF-AML from the multi-ethnic Yunnan Province, China. c-KIT and CEBPA mutations occurred at a higher frequency in CBF-AML cases and were associated with unique clinical characteristics; however, no potential molecular prognostic markers were identified.

No abstract available

These data suggest that genetic driving aberrations may not be the only underlying mechanism of AML development in children. Noncoding drivers, epigenetic changes or environmental influences may play an important role in the final steps towards leukemogenesis.

P2, N=61, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed

Conclusion Here, we report a novel, somatic delins variant in IDH2 , which, albeit affecting the known Arg172 hotspot, does not show susceptibility to the IDH2i enasidenib in-vitro . Our report argues for functional characterisation of novel variants to ensure a valid biomarker-driven therapy in AML patients.

This is the first report on a variant of t (8;21) involving the breakpoint 6p23. After induction chemotherapy, our patient achieved complete remission and has been stable for four years.

The other two patients underwent total body irradiation (TBI) and received cyclophosphamide (CTX) and antilymphocyte globulin (ATG) regimens. Cyclosporine or tacrolimus, mycophenolate mofeil and short-course methorexate were the most frequently administrated graft versus-host disease (GVHD) prophylaxis regimens... Allo-HSCT is an effective therapy among high-risk CBF-AML pediatric patients positive for the RUNX1-RUNX1T1 fusion gene. However, we found that an additional D816 c-KIT mutation is strongly associated with a poor prognosis among these pediatric AML patients.

The assay for transposase-accessible chromatin sequencing of AMLs supported enhanced chromatin accessibilities around genomic regions, such as HOXB cluster genes, SCHIP1, and PRDM16, which were associated with DNA methylation changes in AMLs with FLT3-ITD and high PRDM16 expression. Our results suggest that DNA methylation levels at specific CpG sites are useful to support genetic alterations and gene expression patterns of patients with pediatric AML.

Decitabine, a specific inhibitor of DNA methylation, upregulated the expression of UBXN8 in RUNX1-RUNX1T1 AML cell lines...Enhancing UBXN8 levels can significantly inhibit tumor proliferation and promote the differentiation of RUNX1-RUNX1T1 cells in vivo. In conclusion, our results indicated that epigenetic silencing of UBXN8 via methylation of its promoter region mediated by the RUNX1-RUNX1T1 fusion protein contributes to the leukemogenesis of t(8;21) AML and that UBXN8 targeting may be a potential therapeutic strategy for t(8;21) AML.

AML with RUNX1-RUNX1T1 fusion gene is currently not indicated for transplantation in the first remission. Previous studies have demonstrated that approximately 30% of patients with CBF-AML harbored the KIT mutations at diagnosis, which might be an indicator of poor prognosis. In our study, the KIT mutations were detected much more frequently than in previously studies of newly-diagnosed CBF-AML.

P=N/A, N=200, Recruiting, Acute Leukemia French Association

Conversely, for patients with biallelic CEBPA or DNMT3A mutations, only the MFC method was recommended due to the poor prognostic discriminability in tracking mutant transcripts. In conclusion, this study demonstrated that the MFC MRD after two consolidation cycles independently predicted clinical outcomes, and the integration of MFC and molecular MRD should depend on different types of AML-related genetic lesions.

The present case highlights importance of complex rearrangements rarely encountered in AML, suggesting that all involved regions harbor critical candidate genes regulating the pathogenesis of AML, leading to novel as well as well-known leukemia associated chromosomal aberrations.

Patients older than 65 years represent a particular challenge as many are not candidates for treatment with cytarabine and daunorubicin. Conclusion In this proof of principle study, we demonstrate a novel CRISPR-based technology that effectively inhibits proliferation and decreases tumor volume in vitro and in vivo. Our results suggest that targeting the RUNX1-RUNX1T1 fusion gene can potentially be a future treatment strategy for patients with AML8;21.

First report of t(8;21)(q22;q22) in a patient with CLL. RUNX1-RUNX1T1 fusion gene resulting from the translocation may have played a role in the prolymphocytic transformation.

By summarizing the major findings regarding the cohesin mutation in AML, this review aims to define the characteristics of the cohesin complex mutation, identify its relationships with co-occurring gene mutations, assess its roles in clonal evolution, and discuss its potential for the prognosis of AML. In particular, we focus on the function of cohesin mutations in RUNX1-RUNX1T1 fusion.

P3, N=203, Active, not recruiting, University of Ulm | Recruiting --> Active, not recruiting | Trial primary completion date: Feb 2021 --> Feb 2024

The mechanism for this preferential toxicity was addressed using in vitro replication assays in which DNA polymerase δ was shown to insert Ara-C opposite 8-oxo-dG, resulting in termination of DNA synthesis. Overall, these data suggest that incorporation of Ara-C opposite unrepaired 8-oxo-dG may be the fundamental mechanism conferring selective toxicity and therapeutic effectiveness in OGG1-deficient AML cells.

Finally, ZBTB7A expression in t(8;21) cells lead to a cell cycle arrest that could be mimicked by inhibition of glycolysis. Our findings suggest that loss of ZBTB7A may facilitate the onset of AML t(8;21), and that RUNX1-RUNX1T1-rearranged leukemia might be treated with glycolytic inhibitors.

Even in biological subgroups of AML expected to have sensitive disease, induction failure is not rare. Fortunately, the CBM could identify causes of failure and suggest alternative therapies based on co-occurring genomic abnormalities to mitigate the ineffectiveness of standard induction regimens in patients with resistant disease despite their favorable biology. The identification of patient-specific resistance mechanisms characterizes a new therapeutic imperative founded on deep molecular diagnosis that promises to enhance disease outcomes, inform treatment planning, avoid adverse events from ineffective therapies, and reduce costs.

One course of Homoharringtonine (substitution of Amsacrine in MRC-AML 15 protocol)/ Cytarabine/ Etoposide and one course of Mitoxantrone/ Cytarabine in consolidation chemotherapy were uniform in both groups. EVI1 screening at diagnosis should be included in risk stratification of pediatric AML. Whether pediatric patients with EVI1+ AML can benefit from HSCT in first CR needs further reasearch.

Here we present an unusual case of a core-binding factor leukemia with a CALR mutation. The mutation frequencies point towards a clonal evolution with an initial CALR mutated MPN clone, which acquired further mutations (RUNX1-RUNX1T1 and subsequently DNMT3A and EZH2), leading to secondary AML. Furthermore, CALR LOH may have contributed to the development of extramedullary disease.

Here we present an unusual case of a core-binding factor leukemia with a CALR mutation. The mutation frequencies point towards a clonal evolution with an initial CALR mutated MPN clone, which acquired further mutations (RUNX1-RUNX1T1 and subsequently DNMT3A and EZH2), leading to secondary AML. Furthermore, CALR LOH may have contributed to the development of extramedullary disease.

Here we present an unusual case of a core-binding factor leukemia with a CALR mutation. The mutation frequencies point towards a clonal evolution with an initial CALR mutated MPN clone, which acquired further mutations (RUNX1-RUNX1T1 and subsequently DNMT3A and EZH2), leading to secondary AML. Furthermore, CALR LOH may have contributed to the development of extramedullary disease.