scholarly journals An update on the molecular pathogenesis and potential therapeutic targeting of AML with t(8;21)(q22;q22.1);RUNX1-RUNX1T1

2020 ◽  
Vol 4 (1) ◽  
pp. 229-238 ◽  
Author(s):  
Sayer Al-Harbi ◽  
Mahmoud Aljurf ◽  
Mohamad Mohty ◽  
Fahad Almohareb ◽  
Syed Osman Ali Ahmed
Keyword(s):  
Histone Deacetylases ◽  
Kinase Inhibitors ◽  
Normal Function ◽  
Leukemic Cells ◽  
Proliferative Potential ◽  
Core Binding Factor ◽  
The Core ◽  
Expression Of Genes ◽  
Binding Factor ◽  
Epigenetic Modulation

Abstract Acute myeloid leukemia (AML) with t(8;21)(q22;q22.1);RUNX1-RUNX1T1, one of the core-binding factor leukemias, is one of the most common subtypes of AML with recurrent genetic abnormalities and is associated with a favorable outcome. The translocation leads to the formation of a pathological RUNX1-RUNX1T1 fusion that leads to the disruption of the normal function of the core-binding factor, namely, its role in hematopoietic differentiation and maturation. The consequences of this alteration include the recruitment of repressors of transcription, thus blocking the expression of genes involved in hematopoiesis, and impaired apoptosis. A number of concurrent and cooperating mutations clearly play a role in modulating the proliferative potential of cells, including mutations in KIT, FLT3, and possibly JAK2. RUNX1-RUNX1T1 also appears to interact with microRNAs during leukemogenesis. Epigenetic factors also play a role, especially with the recruitment of histone deacetylases. A better understanding of the concurrent mutations, activated pathways, and epigenetic modulation of the cellular processes paves the way for exploring a number of approaches to achieve cure. Potential approaches include the development of small molecules targeting the RUNX1-RUNX1T1 protein, the use of tyrosine kinase inhibitors such as dasatinib and FLT3 inhibitors to target mutations that lead to a proliferative advantage of the leukemic cells, and experimentation with epigenetic therapies. In this review, we unravel some of the recently described molecular pathways and explore potential therapeutic strategies.

scholarly journals A tool compound targeting the core binding factor Runt domain to disrupt binding to CBFβ in leukemic cells

2017 ◽  
Vol 59 (9) ◽  
pp. 2188-2200 ◽  
Author(s):  
Zaw Min Oo ◽  
Anuradha Illendula ◽  
Jolanta Grembecka ◽  
Charles Schmidt ◽  
Yunpeng Zhou ◽  
...  
Keyword(s):  
Leukemic Cells ◽  
Runt Domain ◽  
Core Binding Factor ◽  
The Core ◽  
Binding Factor

Extracellular KIT receptor mutants, commonly found in core binding factor AML, are constitutively active and respond to imatinib mesylate

Blood ◽  
2005 ◽  
Vol 106 (12) ◽  
pp. 3958-3961 ◽  
Author(s):  
Jörg Cammenga ◽  
Stefan Horn ◽  
Ulla Bergholz ◽  
Gunhild Sommer ◽  
Peter Besmer ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Therapeutic Option ◽  
Extracellular Domain ◽  
Genetic Alterations ◽  
Myelogenous Leukemia ◽  
Core Binding Factor ◽  
Kit Receptor ◽  
Binding Factor

Multiple genetic alterations are required to induce acute myelogenous leukemia (AML). Mutations in the extracellular domain of the KIT receptor are almost exclusively found in patients with AML carrying translocations or inversions affecting members of the core binding factor (CBF) gene family and correlate with a high risk of relapse. We demonstrate that these complex insertion and deletion mutations lead to constitutive activation of the KIT receptor, which induces factor-independent growth of interleukin-3 (IL-3)–dependent cells. Mutation of the evolutionary conserved amino acid D419 within the extracellular domain was sufficient to constitutively activate the KIT receptor, although high expression levels were required. Dose-dependent growth inhibition and apoptosis were observed using either the protein tyrosine kinase inhibitor imatinib mesylate (STI571, Gleevec) or by blocking the phosphoinositide-3-kinase (PI3K)–AKT pathway. Our data show that the addition of kinase inhibitors to conventional chemotherapy might be a new therapeutic option for CBF-AML expressing mutant KIT.

Biophysical characterization of interactions between the core binding factor α and β subunits and DNA

FEBS Letters ◽  
2000 ◽  
Vol 470 (2) ◽  
pp. 167-172 ◽  
Author(s):  
Yen-Yee Tang ◽  
Barbara E. Crute ◽  
John J. Kelley ◽  
Xuemei Huang ◽  
Jiangli Yan ◽  
...  
Keyword(s):  
Core Binding Factor ◽  
Biophysical Characterization ◽  
The Core ◽  
Binding Factor ◽  
Α And Β Subunits ◽  
Factor Α

Adverse Prognostic Significance of KIT Mutations in Adult Acute Myeloid Leukemia With inv(16) and t(8;21): A Cancer and Leukemia Group B Study

2006 ◽  
Vol 24 (24) ◽  
pp. 3904-3911 ◽  
Author(s):  
Peter Paschka ◽  
Guido Marcucci ◽  
Amy S. Ruppert ◽  
Krzysztof Mrózek ◽  
Hankui Chen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Direct Sequencing ◽  
Prognostic Significance ◽  
Prognostic Impact ◽  
Core Binding Factor ◽  
Relapse Risk ◽  
Binding Factor ◽  
Acute Myeloid

Purpose To analyze the prognostic impact of mutated KIT (mutKIT) in core-binding factor acute myeloid leukemia (AML) with inv(16)(p13q22) and t(8;21)(q22;q22). Patients and Methods Sixty-one adults with inv(16) and 49 adults with t(8;21), assigned to postremission therapy with repetitive cycles of higher dose cytarabine were analyzed for mutKIT in exon 17 (mutKIT17) and 8 (mutKIT8) by denaturing high-performance liquid chromatography and direct sequencing at diagnosis. The median follow-up was 5.3 years. Results Among patients with inv(16), 29.5% had mutKIT (16% with mutKIT17 and 13% with sole mutKIT8). Among patients with t(8;21), 22% had mutKIT (18% with mutKIT17 and 4% with sole mutKIT8). Complete remission rates of patients with mutKIT and wild-type KIT (wtKIT) were similar in both cytogenetic groups. In inv(16), the cumulative incidence of relapse (CIR) was higher for patients with mutKIT (P = .05; 5-year CIR, 56% v 29%) and those with mutKIT17 (P = .002; 5-year CIR, 80% v 29%) compared with wtKIT patients. Once data were adjusted for sex, mutKIT predicted worse overall survival (OS). In t(8;21), mutKIT predicted higher CIR (P = .017; 5-year CIR, 70% v 36%), but did not influence OS. Conclusion We report for the first time that mutKIT, and particularly mutKIT17, confer higher relapse risk, and both mutKIT17 and mutKIT8 appear to adversely affect OS in AML with inv(16). We also confirm the adverse impact of mutKIT on relapse risk in t(8;21) AML. We suggest that patients with core-binding factor AML should be screened for mutKIT at diagnosis for both prognostic and therapeutic purposes, given that activated KIT potentially can be targeted with novel tyrosine kinase inhibitors.

The core-binding factor β subunit is required for bone formation and hematopoietic maturation

2002 ◽  
Vol 32 (4) ◽  
pp. 645-649 ◽  
Author(s):  
Janelle Miller ◽  
Alan Horner ◽  
Terryl Stacy ◽  
Christopher Lowrey ◽  
Jane B. Lian ◽  
...  
Keyword(s):  
Bone Formation ◽  
Β Subunit ◽  
Core Binding Factor ◽  
The Core ◽  
Binding Factor

Expression of Core-Binding Factor (CBF) Fusion Genes in Clonal Evolution of Chronic Myeloid Leukemia (CML).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4697-4697
Author(s):  
Farhad Ravandi-Kashani ◽  
Hagop Kantarjian ◽  
Stefan Faderl ◽  
Susan O’Brien ◽  
Mary B. Rios ◽  
...  
Keyword(s):  
Disease Progression ◽  
Myeloid Leukemia ◽  
Clonal Evolution ◽  
Chronic Phase ◽  
Survival Advantage ◽  
Leukemic Cells ◽  
Fusion Genes ◽  
Core Binding Factor ◽  
Blast Phase ◽  
Binding Factor

Abstract A “2-hit” model of leukemogenesis has been proposed in which one class of mutations confers a proliferative or survival advantage to the cells and the second class serves primarily to interfere with hematopoietic cell differentiation. In support of this, FLT3 receptor mutations have been frequently reported in patients with t(8;21) and inv(16) acute myeloid leukemia (AML), otherwise known as core-binding factor (CBF) leukemias, whose fusion gene products (AML1-ETO and CBFB-MYH11) contribute to impaired differentiation of leukemic cells. In CML, enhanced kinase activity of BCR-ABL confers a proliferative and survival advantage to the leukemic cells and clonal evolution is a common event at the time of disease acceleration. However, the acquisition of CBF fusion genes has not been commonly reported during the clonal evolution of CML. We report 4 patients with CML who developed CBF type rearrangements [inv(16)(n=2) and t(8;21)(n=2)] at the time of disease progression. Patient #1, a 61 year old female, presented with myeloid blast phase disease with 46,XX,t(9;22)(q34;q11.2),inv(16)(p13q22) and was treated with imatinib achieving a hematological but not cytogenetic response. Patient #2, a 48 year old male, presented with chronic phase disease and received imatinib for 2 years, achieved a complete cytogenetic remission (CG CR) but progressed to blast phase with development of 46,XY,t(9;22)(q34;q11.2),inv(16)(p13q22). Both patients had elevated and abnormal marrow eosinophils at the time of clonal evolution. Patient #3, a 54 year old female, presented in chronic phase, received imatinib and achieved CG CR after 3 months. Blast transformation occurred after one year with 48, XX,+8,t(8;21)(q22;q22),t(9;22;19;10)(q34;q11;p13.1;q22),+der(22)t(9;22;19;10). Patient #4, a 47 year old male, presented with an extramedullary myeloid mass on his arm and features of chronic phase in the marrow examination. He was treated with troxacitabine with resolution of the mass. He was then treated with imatinib. Ten months later he developed a recurrent mass with cytogenetic studies of both the mass and marrow showing 47,XY,+8,t(8;21)(q22;q22),del(9)(q13q32),t(9;22)(q34;q11.2). To our knowledge, eleven other patients with CML with inv(16)(n=10) or with t(8;21)(n=1) have been previously reported in the literature, none treated with imatinib. Patients with inv(16) had features of AML with eosinophilia (FAB M4Eo) demonstrating dysplastic eosinophils in the bone marrow examination. Development of the CBF rearrangement was invariably associated with disease progression into the myeloid blast phase with the exception of one patient, reported to develop lymphoid blast phase, based on surface markers. CBF rearrngements occur rarely at the time of disease progression in CML and may contribute to disease transformation based on the “2-hit” hypothesis for leukemogenesis.

The Histone Deacetylase Inhibitor (HDI) Depsipeptide Has Differential Activity in Core Binding Factor AML.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1956-1956 ◽  
Author(s):  
Olatoyosi M. Odenike ◽  
Serhan Alkan ◽  
Dorie Sher ◽  
John E. Godwin ◽  
Dezheng Huo ◽  
...  
Keyword(s):  
Histone Deacetylases ◽  
Target Genes ◽  
Antileukemic Activity ◽  
Core Binding Factor ◽  
Specific Target ◽  
Binding Factor ◽  
Objective Evidence ◽  
Group A ◽  
Group B ◽  
H3 Acetylation

Abstract Recruitment of histone deacetylases and CpG island methylation at promoter regions of specific genes are two mechanisms of epigenetic silencing which have been linked and are implicated in differentiation block in AML. We hypothesized that the HDI depsipeptide could cause transcriptional de-repression and upregulation of specific target genes in AML, with subsequent differentiation of the leukemic clone. Twenty-one patients (pts), median age 60 years (range 25–77) were enrolled on a multicenter Phase II study of depsipeptide in AML. Pts were stratified into 2 groups on study entry: Group A (n= 14) included pts without specific chromosomal abnormalities known to recruit histone deacetylases. Group B (n=7) included pts with chromosomal aberrations such as the t(8;21) and inv 16 known to recruit histone deacetylases. All 7 pts in cohort B had translocations involving CBFα or AML1 (n=6) or CBFβ (n=1). Depsipeptide was administered intravenously at a dose of 13mg/m2/d on days 1, 8 and 15 of a 28 day cycle. Peripheral blood mononuclear cells were obtained prior to, and after 4 and 24 hrs, on days 1 and 8 of the first cycle of therapy for evaluation of histone (H3) acetylation by flow cytometry, and gene re-expression by Quantitatative real-time RT-PCR (RQ-PCR). Target genes of interest include MDR1, a target of HDI mediated upregulation, p15INK4B(p15) a target of DNA hypermethylation in AML, and p14ARF (p14), a target of AML1-ETO mediated transcriptional repression. H3 acetylation at the p15 and MDR1 promoters was analyzed by chromatin immunoprecipitation, followed by Q- PCR. The most common adverse effects noted included grade 1/2 nausea, vomiting and fatigue. No objective evidence of response (CR or PR) or other evidence of antileukemic activity has been seen in group A. In contrast, in group B, antileukemic activity has been observed in 4 of 7 (57%) of pts. These include 2 pts with clearance of bone marrow (BM) blasts in the setting of a normocellular marrow, and 2 other pts with a significant decrease (>50% decrease) BM blasts. This effect was short-lived, with all 4 pts developing evidence of disease progression within 30 days of the initial response. Interestingly 5 of 7 pts (including all 4 pts with evidence of an antileukemic response) in cohort B demonstrated an increase in global H3 acetylation at 4 and/or 24 hrs, in contrast to 4 of 14 pts (28%) in cohort A. Furthermore, in cohort B, at 24hrs, there was a 75% mean increase in MDR1 expression (p=0.005), a 162% mean increase in p15 (p=0.01) and a 106% mean increase in p14 (p<0.0001). Although there was a trend towards upregulation of MDR1, p15 and p14 expression by hr 24 in cohort A (41%, 29% and 34% mean increase in expression respectively), these changes were not statistically significant. In 4 pts analyzed, there was evidence of an increase in H3 acetylation by hr 4 at the MDR1 promoter (p=0.03) and at the p15 promoter (p=0.02). We conclude that the HDI, depsipeptide, may have anti-leukemic activity in Core Binding Factor AML, and this is associated with a concomitant increase in histone acetylation and upregulation of specific target genes. Further development of this agent in this subset of AML should focus on combination strategies particularly those that involve other agents that target epigenetic changes such as DNA hypomethylating agents.

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