Dependency of B-Cell Acute Lymphoblastic Leukemia and Multiple Myeloma Cell Lines on MEN1 Extends beyond MEN1–KMT2A Interaction
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SUBMITTER: Wolffhardt T
PROVIDER: S-EPMC10670986 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
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Project description:Background/aimPrevious reports have associated the KMT2A-ELL fusion gene, generated by t(11;19)(q23;p13.1), with acute myeloid leukemia (AML). We herein report a KMT2A-ELL and a novel ZNF56-KMT2A fusion genes in a pediatric T-lineage acute lymphoblastic leukemia (T-ALL).Materials and methodsGenetic investigations were performed on bone marrow of a 13-year-old boy diagnosed with T-ALL.ResultsA KMT2A-ELL and a novel ZNF56-KMT2A fusion genes were generated on der(11)t(11;19)(q23;p13.1) and der(19)t(11;19)(q23;p13.1), respectively. Exon 20 of KMT2A fused to exon 2 of ELL in KMT2A-ELL chimeric transcript whereas exon 1 of ZNF56 fused to exon 21 of KMT2A in ZNF56-KMT2A transcript. A literature search revealed four more T-ALL patients carrying a KMT2A-ELL fusion. All of them were males aged 11, 11, 17, and 20 years.ConclusionKMT2A-ELL fusion is a rare recurrent genetic event in T-ALL with uncertain prognostic implications. The frequency and impact of ZNF56-KMT2A in T-ALL are unknown.
| S-EPMC7943214 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-06-05 | GSE151823 | GEO
Project description:The role of allogeneic hematopoietic stem cell transplantation (HSCT) for infants with acute lymphoblastic leukemia (ALL) and KMT2A gene rearrangement (KMT2A-r) is controversial in terms of both its efficacy and potential for acute and late toxicities. In Japanese Pediatric Leukemia/Lymphoma Study Group trial MLL-10, by introducing intensive chemotherapy, indication of HSCT was restricted to patients with high-risk (HR) features only (KMT2A-r and either age <180 days or presence of central nervous system leukemia). Of the 56 HR patients, 49 achieved complete remission. Forty-three patients received HSCT in first remission including 38 patients receiving protocol-specified HSCT with conditioning consisting of individualized targeted doses of busulfan, etoposide, and cyclophosphamide. Three-year event-free survival (EFS) of 56.8% (95% confidence interval [CI], 42.4% to 68.8%) and overall survival of 80.2% (95% CI, 67.1% to 88.5%) were accomplished. Univariable analysis showed that Interfant-HR criteria and flow cytometric minimal residual disease (MRD; ≥0.01%), both at the end of induction and at the end of consolidation (EOC), were significantly associated with poorer EFS. In the multivariable analysis, positive MRD at EOC was solely associated with poor EFS (P < .001). Rapid pretransplant MRD clearance and tailored HSCT strategy in the MLL-10 trial resulted in a favorable outcome for infants with HR KMT2A-r ALL. However, considering the high rate of potentially life-threatening toxicities and the risk of late effects, its indication should be further restricted or even eliminated in the future by introducing more effective therapeutic modalities with minimal toxicities. This trial was registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) as #UMIN000004801.
| S-EPMC8679679 | biostudies-literature
Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with a high incidence of relapse. Here we show that Runt-related transcription factor 2, RUNX2 is upregulated in high-risk T-ALL with KMT2A rearrangements (KMT2A-R) or immature phenotype. In KMT2A-R cells, we identified RUNX2 as a direct target of the KMT2A chimeras, while it reciprocally binds the KMT2A promoter, establishing a regulatory feed-forward mechanism. Notably, RUNX2 is required for survival in immature and KMT2A-R T-ALL in vitro and in vivo. We report a direct transcriptional regulation of CXCR4 signaling by RUNX2, which thereby promotes cell migration and adhesion. Functionally, RUNX2 impacts T-ALL cell homing and exacerbates T-ALL progression to medullary and extramedullary sites. We demonstrate that RUNX2 enables these energy-demanding processes by increasing metabolic activity in T-ALL cells through positive regulation of both glycolysis and oxidative phosphorylation. Concurrently, RUNX2 upregulation results in increased mitochondrial dynamics and biogenesis in T-ALL cells. As a proof of concept, immature and KMT2A-R T-ALL cells are vulnerable to pharmacological targeting of the interaction of RUNX2 with its co-factor CBFβ. In conclusion, we identify RUNX2 a dependency factor in immature and KMT2A-R T-ALL that regulates cell metabolism and disease progression
2020-06-05 | GSE151822 | GEO
Project description:KMT2A-rearranged infant ALL is an aggressive childhood leukemia with poor prognosis. Here, we investigated the developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia (B-ALL) using bulk messenger RNA (mRNA) meta-analysis and examination of single lymphoblast transcriptomes against a developing bone marrow reference. KMT2A-rearranged infant B-ALL was uniquely dominated by an early lymphocyte precursor (ELP) state, whereas less adverse NUTM1-rearranged infant ALL demonstrated signals of later developing B cells, in line with most other childhood B-ALLs. We compared infant lymphoblasts with ELP cells and revealed that the cancer harbored hybrid myeloid-lymphoid features, including nonphysiological antigen combinations potentially targetable to achieve cancer specificity. We validated surface coexpression of exemplar combinations by flow cytometry. Through analysis of shared mutations in separate leukemias from a child with infant KMT2A-rearranged B-ALL relapsing as AML, we established that KMT2A rearrangement occurred in very early development, before hematopoietic specification, emphasizing that cell of origin cannot be inferred from the transcriptional state.
| S-EPMC9018413 | biostudies-literature
Project description:Rearrangments in Histone-lysine-N-methyltransferase 2A (KMT2Ar) are associated with pediatric, adult and therapy-induced acute leukemias. Infants with KMT2Ar acute lymphoblastic leukemia (ALL) have a poor prognosis with an event-free-survival of 38%. Herein we evaluate 1116 FDA approved compounds in primary KMT2Ar infant ALL specimens and identify a sensitivity to proteasome inhibition. Upon exposure to this class of agents, cells demonstrate a depletion of histone H2B monoubiquitination (H2Bub1) and histone H3 lysine 79 dimethylation (H3K79me2) at KMT2A target genes in addition to a downregulation of the KMT2A gene expression signature, providing evidence that it targets the KMT2A transcriptional complex and alters the epigenome. A cohort of relapsed/refractory KMT2Ar patients treated with this approach on a compassionate basis had an overall response rate of 90%. In conclusion, we report on a high throughput drug screen in primary pediatric leukemia specimens whose results translate into clinically meaningful responses. This innovative treatment approach is now being evaluated in a multi-institutional upfront trial for infants with newly diagnosed ALL.
| S-EPMC9925443 | biostudies-literature
Project description:Dysregulation of the intrinsic BCL-2 pathway-mediated apoptosis cascade is a common feature of hematological malignancies including acute B-lymphoblastic leukemia (B-ALL). The KMT2A-rearranged high-risk cytogenetic subtype is characterized by high expression of antiapoptotic protein BCL-2, likely due to the direct activating binding of KMT2A fusion proteins to the BCL2 gene. The BCL-2 inhibitor venetoclax (VEN) has proven great clinical value in other blood cancers, however, data on B-ALL is sparse and past studies have not so far described the effects of VEN on gene and protein expression profiles. Using cell lines and patient-derived in vivo xenograft models, we show BCL-2 pathway-mediated apoptosis induction and decelerated tumor cell counts in KMT2A-rearranged B-ALL but not in other cytogenetic subtypes. VEN treatment of cell line- and patient-derived xenografts reduced blast frequencies in blood, bone marrow, and spleen, and tumor cell doubling times were increased. Growth rates are further correlated with VEN concentrations in blood. In vitro incubation with VEN resulted in BCL-2 dephosphorylation and targeted panel RNA sequencing revealed reduced gene expression of antiapoptotic pathway members BCL2, MCL1, and BCL2L1 (BCL-XL). Reinforced translocation of BAX proteins towards mitochondria induced caspase activation and cell death commitment. Prolonged VEN application led to upregulation of antiapoptotic proteins BCL-2, MCL-1, and BCL-XL. Interestingly, the extrinsic apoptosis pathway was strongly modulated in SEM cells in response to VEN. Gene expression of members of the tumor necrosis factor signaling cascade was increased, resulting in canonical NF-kB signaling. This possibly suggests a previously undescribed mechanism of BCL-2-independent and NF-kB-mediated upregulation of MCL-1 and BCL-XL. In summary, we herein prove that VEN is a potent option to suppress tumor cells in KMT2A-rearranged B-ALL in vitro and in vivo. Possible evasion mechanisms, however, must be considered in subsequent studies.
| S-EPMC9249764 | biostudies-literature
Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with a high incidence of relapse. Here we show that Runt-related transcription factor 2, RUNX2 is upregulated in high-risk T-ALL with KMT2A rearrangements (KMT2A-R) or immature phenotype. In KMT2A-R cells, we identified RUNX2 as a direct target of the KMT2A chimeras, while it reciprocally binds the KMT2A promoter, establishing a regulatory feed-forward mechanism. Notably, RUNX2 is required for survival in immature and KMT2A-R T-ALL in vitro and in vivo. We report a direct transcriptional regulation of CXCR4 signaling by RUNX2, which thereby promotes cell migration and adhesion. Functionally, RUNX2 impacts T-ALL cell homing and exacerbates T-ALL progression to medullary and extramedullary sites. We demonstrate that RUNX2 enables these energy-demanding processes by increasing metabolic activity in T-ALL cells through positive regulation of both glycolysis and oxidative phosphorylation. Concurrently, RUNX2 upregulation results in increased mitochondrial dynamics and biogenesis in T-ALL cells. As a proof of concept, immature and KMT2A-R T-ALL cells are vulnerable to pharmacological targeting of the interaction of RUNX2 with its co-factor CBFβ. In conclusion, we identify RUNX2 a dependency factor in immature and KMT2A-R T-ALL that regulates cell metabolism and disease progression
2020-06-05 | GSE151819 | GEO
Project description: Not available
| S-EPMC11216977 | biostudies-literature
Project description:BackgroundInfants with KMT2A-rearranged B-cell precursor acute lymphoblastic leukemia (ALL) have poor outcomes. There is an urgent need to identify novel agents to improve survival. Proteasome inhibition has emerged as a promising therapeutic strategy for several hematological malignancies. The aim of this study was to determine the preclinical efficacy of the selective proteasome inhibitor carfilzomib, for infants with KMT2A-rearranged ALL.MethodsEight infant ALL cell lines were extensively characterized for immunophenotypic and cytogenetic features. In vitro cytotoxicity to carfilzomib was assessed using a modified Alamar Blue assay with cells in logarithmic growth. The Bliss Independence model was applied to determine synergy between carfilzomib and the nine conventional chemotherapeutic agents used to treat infants with ALL. Established xenograft models were used to identify the maximal tolerated dose of carfilzomib and determine in vivo efficacy.ResultsCarfilzomib demonstrated low IC50 concentrations within the nanomolar range (6.0-15.8 nm) across the panel of cell lines. Combination drug testing indicated in vitro synergy between carfilzomib and several conventional chemotherapeutic agents including vincristine, daunorubicin, dexamethasone, L-asparaginase, and 4-hydroperoxycyclophosphamide. In vivo assessment did not lead to a survival advantage for either carfilzomib monotherapy, when used to treat both low or high disease burden, or for carfilzomib in combination with multi-agent induction chemotherapy comprising of vincristine, dexamethasone, and L-asparaginase.ConclusionsOur study highlights that in vitro efficacy does not necessarily translate to benefit in vivo and emphasizes the importance of in vivo validation prior to suggesting an agent for clinical use. Whilst proteasome inhibitors have an important role to play in several hematological malignancies, our findings guard against prioritization of carfilzomib for treatment of KMT2A-rearranged infant ALL in the clinical setting.
| S-EPMC8082024 | biostudies-literature