IKZF1 ＡＭＬ

Reducing casein kinase 1α (CK1α) expression inhibits the growth of multiple cancer cell lines, making it a potential therapeutic target for cancer. Herein, we evaluated the anti-tumor activity of FPFT-2216-a novel low molecular weight compound-in lymphoid tumors and elucidated its molecular mechanism of action. Additionally, we determined whether targeting CK1α with FPFT-2216 is useful for treating hematopoietic malignancies. FPFT-2216 strongly degraded CK1α and IKAROS family zinc finger 1/3 (IKZF1/3) via proteasomal degradation...

INTRODUCTION: A variety of gene rearrangements and molecular alterations are key drivers in the pathobiology of acute leukemia and myeloid disorders; current classification systems increasingly incorporate these findings in diagnostic algorithms. Therefore, clinical laboratories require versatile tools, which can detect an increasing number and variety of molecular and cytogenetic alterations of clinical significance. METHODS: We validated an RNA-based NGS assay that enables the detection of: i) numerous hybrid fusion transcripts (including rare/novel gene partners), ii) aberrantly expressed EVI1(MECOM) and IKZF1 (Del Exons 4-7) transcripts, and iii) hotspot variants in KIT, ABL1, NPM1 (relevant in the context of gene rearrangement status)...

To reducing chemotherapy-related toxicity, the chemo-free regimens become a new trend of Ph + ALL treatment. Therefore, we conducted a phase 2 trial of dasatinib plus prednisone, as induction (Course I) and early consolidation (Courses II and III) treating newly diagnosed Ph + ALL. The trial was registered at www.chictr.org.cn, ChiCTR2000038053. Forty-one patients were enrolled from 15 hospitals. The complete remission (CR) was 95% (39/41), including two elderly induction deaths...

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease that causes obstructed airflow from the lungs. DNA methylation can regulate gene expression. Understanding the potential molecular mechanism of COPD is of great importance. The aim of this study was to find differentially methylated/expressed genes in COPD. DNA methylation and gene expression profiles in COPD were downloaded from the dataset, followed by functional analysis of differentially-methylated/expressed genes. The potential diagnostic value of these differentially-methylated/expressed genes was determined by receiver operating characteristic (ROC) analysis...

We analyzed the pattern of whole-genome copy number alterations (CNAs) and their association with the kinetics of blast clearance during the induction treatment among 195 pediatric patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) who displayed intermediate or high levels of minimal residual disease (MRD). Using unsupervised hierarchical clustering of CNAs > 5 Mbp, we dissected three clusters of leukemic samples with distinct kinetics of blast clearance [A - early slow responders (n=105), B - patients with persistent leukemia (n=24), C - fast responders with the low but detectable disease at the end of induction (n=66)] that corresponded with the patients' clinical features, the microdeletion profile,the presence of gene fusions and patients survival...

Plasmacytoid Dendritic Cells (pDC) are type I interferon (IFN)-producing cells that play a key role in immune responses. Two major types of neoplastic counterparts for pDC are now discriminated: Blastic pDC Neoplasm (BPDCN) and Mature pDC Proliferation (MPDCP), associated with myeloid neoplasm. Two types of MPDCP are now better described: Chronic MyeloMonocytic Leukemia with pDC expansion (pDC-CMML) and Acute Myeloid Leukemia with pDC expansion (pDC-AML). Differential diagnosis between pDC-AML and BPDCN is particularly challenging, and genomic features can help for diagnosis...

BACKGROUND: The risk of recurrence after completion of curative-intent treatment of colorectal cancer (CRC) is hard to predict. Post-treatment assaying for circulating tumor DNA (ctDNA) is an encouraging approach for stratifying patients for therapy, but the prognostic value of this approach is less explored. This study aimed to determine if detection of methylated BCAT1 and IKZF1 following completion of initial treatment identified patients with a poorer recurrence-free survival (RFS)...

Great progress has been made in improving survival in multiple myeloma (MM) patients over the last 30 years. New drugs have been introduced and complete responses are frequently seen. However, the majority of MM patients do experience a relapse at a variable time after treatment, and ultimately the disease becomes drug-resistant following therapies. Recently, minimal residual disease (MRD) detection has been introduced in clinical trials utilizing novel therapeutic agents to measure the depth of response. MRD can be considered as a surrogate for both progression-free and overall survival...

OBJECTIVES: Iberdomide is a high-affinity cereblon ligand that promotes proteasomal degradation of transcription factors Ikaros ( IKZF1 ) and Aiolos ( IKZF3 ). Pharmacodynamics and pharmacokinetics of oral iberdomide were evaluated in a phase 2b study of patients with active systemic lupus erythematosus (SLE). METHODS: Adults with autoantibody-positive SLE were randomised to placebo (n=83) or once daily iberdomide 0.15 mg (n=42), 0.3 mg (n=82) or 0.45 mg (n=81)...

The strongest predictors of outcome in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) are minimal residual disease (MRD) and specific molecular abnormalities. One unfavorable prognostic factor is the presence of IKZF1 gene aberrations, particularly when co-occurring with high MRD level at the end of induction treatment. The present study determines the predictive value of a recently-defined IKZF1-plus (IKZF1plus ) microdeletion profile in 373 children with BCP-ALL treated according to the ALL-intercontinental Berlin-Frankfurt-Munster protocol 2009 protocol...

The thalidomide analogue lenalidomide (Len) is a clinical therapeutic that alters the substrate engagement of cereblon (CRBN), a substrate receptor for the CRL4 E3 ubiquitin ligase. Here, we report the development of photolenalidomide (pLen), a Len probe with a photoaffinity label and enrichment handle, designed for target identification by chemical proteomics. pLen preserves the substrate degradation profile, phenotypic antiproliferative and immunomodulatory properties of Len, and enhances interactions with the thalidomide-binding domain of CRBN, as revealed by binding site mapping and molecular modeling...

Despite being predominantly a childhood disease, the incidence of acute lymphoblastic leukemia (ALL) has a second peak in adults aged 60 years and over. These older adults fare extremely poorly with existing treatment strategies and very few studies have undertaken a comprehensive genetic and genomic characterization to improve prognosis in this age group. We performed cytogenetic, single nucleotide polymorphism (SNP) array and next-generation sequencing (NGS) analyses on samples from 210 patients aged ≥60 years from the UKALL14 and UKALL60+ clinical trials...

Chromosomal abnormalities are established prognostic markers in adult ALL. We assessed the prognostic impact of established chromosomal abnormalities and key copy number alterations (CNA) among 652 patients with B-cell precursor ALL treated on a modern MRD driven protocol. Patients with KMT2A-AFF1, complex karyotype (CK) and low hypodiploidy/near-triploidy (HoTr) had high relapse rates 50%, 60% & 53% and correspondingly poor survival. Patients with BCR-ABL1 had an outcome similar to other patients. JAK-STAT abnormalities (CRLF2, JAK2) occurred in 6% patients and were associated with a high relapse rate (56%)...

Targeted protein degradation by the ubiquitin-proteasome system represents a new strategy to destroy pathogenic proteins in human diseases, including cancer and neurodegenerative diseases. The immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide have revolutionized the treatment of patients with multiple myeloma (MM) and other hematologic malignancies, but almost all patients eventually develop resistance to IMiDs. CRBN, a substrate receptor of CUL4-RBX1-DDB1-CRBN (CRL4CRBN ) E3 ubiquitin ligase, is a direct target for thalidomide teratogenicity and antitumor activity of IMiDs (now known as Cereblon E3 ligase modulators: CELMoDs)...

BACKGROUND: Standard therapy for human epidermal growth factor receptor 2 (HER2)-mutant non-small-cell lung cancer (NSCLC) is lacking. The clinical benefits with pan-HER inhibitors (afatinib, neratinib, and dacomitinib), anti-HER2 antibody drug conjugate (ADC) trastuzumab emtansine, and an emerging irreversible tyrosine kinase inhibitor (TKI) poziotinib were modest. Another new ADC trastuzumab deruxtecan showed encouraging outcomes, but only phase I study was completed. Pyrotinib, another emerging irreversible epidermal growth factor receptor (EGFR)/HER2 dual TKI, has been approved in HER2-positive breast cancer in 2018 in China...

IKZF1 deletions (ΔIKZF1) are commonly detected in B-precursor acute lymphoblastic leukemia (ALL; B-ALL) and are widely assumed to have a significant impact on outcome. We compared the ability of multiplex ligand-dependent probe amplification (MLPA) and polymerase chain reaction (PCR) to detect ΔIKZF1 and to determine the impact on event-free survival of patients with precursor B-ALL aged 23 to 65 years recruited to the completed trial UKALL14 (ISRCTN 66541317). From 655 recruits with BCR-ABL1+ and BCR-ABL1- B-ALL, all available diagnostic DNA samples (76% of the recruited population) were screened by multiplex end point PCR covering 4 deletions: dominant-negative (DN) Δ4-7 or the loss of function Δ2-7, Δ4-8, and Δ2-8 (n = 498), MLPA (n = 436), or by both (n = 420)...

We present our data of a novel proposed CNA-profile risk-index, applied on a Greek ALLIC-BFM-treated cohort, aiming at further refining genomic risk-stratification. Eighty-five of 227 consecutively treated ALL patients were analyzed for the copy-number-status of eight genes (IKZF1/CDKN2A/2B/PAR1/BTG1/EBF1/PAX5/ETV6/RB1). Using the MLPA-assay, patients were stratified as: (1) Good-risk(GR)-CNA-profile ( n = 51), with no deletion of IKZF1/CDKN2A/B/PAR1/BTG1/EBF1/PAX5/ETV6/RB1 or isolated deletions of ETV6/PAX5/BTG1 or ETV6 deletions with a single additional deletion of BTG1/PAX5/CDKN2A/B...

PURPOSE: The efficacy of EZH2 inhibition has been modest in the initial clinical exploration of diffuse large B-cell lymphoma (DLBCL), yet EZH2 inhibitors are well tolerated. Herein, we aimed to uncover genetic and pharmacological opportunities to enhance the clinical efficacy of EZH2 inhibitors in DLBCL. EXPERIMENTAL DESIGN: We conducted a genome-wide sensitizing CRISPR/Cas9 screen with tazemetostat, a catalytic inhibitor of EZH2. The sensitizing effect of IKZF1 loss-of-function was then validated and leveraged for combination treatment with lenalidomide...

The long-term prognosis of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) is still unsatisfactory even after the emergence of tyrosine kinase inhibitors (TKIs) against chimeric BCR-ABL, and this is associated with the high incidence of genetic alterations of Ikaros family zinc finger 1 (IKZF1), most frequently the hemi-allelic loss of exons 4-7 expressing a dominant-negative isoform Ik6. We found that lenalidomide (LEN), a representative of immunomodulatory drugs (IMiDs), which have been long used for the treatment of multiple myeloma, specifically induced accumulation of Ik6 with the disappearance of functional isoforms within 24 h (i...

Genomic classification has improved risk assignment of pediatric, but not adult B-lineage acute lymphoblastic leukemia (B-ALL). The international UKALLXII/ECOG-ACRIN E2993 (#NCT00002514) trial accrued 1229 adolescent/adult patients with BCR-ABL1- B-ALL (aged 14 to 65 years). Although 93% of patients achieved remission, 41% relapsed at a median of 13 months (range, 28 days to 12 years). Five-year overall survival (OS) was 42% (95% confidence interval, 39, 44). Transcriptome sequencing, gene expression profiling, cytogenetics, and fusion polymerase chain reaction enabled genomic subtyping of 282 patient samples, of which 264 were eligible for trial, accounting for 64...