IKZF1 mutation

The utilization of RNA-seq enables the identification of clinically significant genetic abnormalities that may go undetected through conventional detection methods. Its robust analytical performance might bring great application value for clinical diagnosis, prognosis, and therapy in ALL.

P2, N=9, Terminated, Memorial Sloan Kettering Cancer Center | Trial completion date: Jul 2024 --> Mar 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Jul 2024 --> Mar 2024; Low accrual

HCT was well-tolerated achieving full engraftment in both patients receiving reduced intensity, matched unrelated donor grafts, with no severe acute or chronic graft-vs-host-disease, and in remission from their diseases 2.5 and 4 years post-HCT, respectively. These results suggest that HCT is a valid and curative option in patients with IKAROS GOF disease and severe clinical manifestations.

Auto-HSCT may be an attractive treatment for B-ALL patients of IKZF1 mutation with negative MRD after three chemotherapy cycles. The adverse impact of IKZF1 on prognosis may be overcome by auto-HSCT.

While many therapies are under investigation including the addition of a tyrosine kinase inhibitor or ruxolitinib to conventional chemotherapy, a standardized and molecularly-based approach to treating patients with Ph-like ALL is not yet defined. There also remain questions about the efficacy of integrating inotuzumab ozogamicin or blinatumomab into first-line therapy for these patients...1 patient received Car T cell therapy with Brexucabtagene autoleucel following relapse after allogeneic stem cell transplant... We identified 9 patients who met inclusion criteria. All 9 patients self-identified as either ‘American Indian or Alaska Native’ or ‘Hispanic or Latino. ‘ The median age at diagnosis was 34 and the mean BMI at diagnosis was 34.

These dismal outcomes are only partially explained by the hotspot mutation N159S. Our findings suggest a role for IKZF1 mutation status in AML risk modeling.

P=N/A, N=44, Completed, Memorial Sloan Kettering Cancer Center | Active, not recruiting --> Completed | Trial completion date: Aug 2024 --> Nov 2023 | Trial primary completion date: Aug 2024 --> Nov 2023

PTPN11 is associated with distinct clinical and molecular characteristics, and adverse prognosis in AML patients.

Therefore, the inclusion of CREBBP mutated patients in very low risk protocols should be carefully evaluated. The validation of these findings is ongoing through the analysis of patients treated by other international study groups adopting different chemotherapy backbones.

With >2 years of follow-up in the phase 3 ASCEMBL study, asciminib (ASC) has continued to demonstrate superior efficacy vs bosutinib (BOS) in pts with CML-CP after ≥2 prior TKIs, and analysis of cancer gene somatic mutations in this population has the potential to reveal additional insights into pts' response to study treatments or characteristics of the disease in later lines of therapy... Adults with CML-CP previously treated with ≥2 TKIs with intolerance of their last TKI or lack of efficacy per 2013 European LeukemiaNet recommendations and without BCR::ABL1 T315I or V299L mutations were randomized 2:1 to ASC 40 mg twice daily or BOS 500 mg once daily... ASXL1 mutations are most frequently detected at CML diagnosis and were enriched at BL in this study of pts with CML-CP previously treated with ≥2 TKIs, which is consistent with a role in TKI resistance. RUNX1 and IKZF1 mutations, which are associated with progression to accelerated or blast phase in CML, were very rare in this pt population, supporting their role in CML disease progression. The high frequency of co-occurrence of BCR::ABL1 mutations and blood cancer gene mutations in CML-CP is an important finding since cancer gene mutations could modify response to TKIs in individual pts.

Single-cell analysis reveals that Ikaros modulates core transcriptional programs in TECs that correlate with the observed cellular changes. Our findings highlight a previously undescribed role for Ikaros in regulating epithelial lineage development and function and suggest that failed thymic central tolerance could contribute to the autoimmunity seen in humans with IKZF1 mutations.

P=N/A, N=44, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Aug 2023 --> Aug 2024 | Trial primary completion date: Aug 2023 --> Aug 2024

Jude protocol for outpatient delivery, including once weekly daunorubicin and vincristine in initial therapy, postponing intrathecal chemotherapy until day 22, prophylactic oral antibiotics/ anti-mycotics, use of generic drugs, and no central nervous system radiation. Outcomes were comparable to those reported in the control arm of the Total Therapy XI study but inferior to current treatment protocols in high-income countries. Using an outpatient- based modification of the St. Jude Total XI protocol, we obtained good results with relatively few hospitalizations or adverse events and substantial savings.

Outlier isoforms were also effective targeted RNA markers for PAX5 intragenic amplifications (B-ALL), KMT2A-PTD (myeloid malignancies), and rare NOTCH1 intragenic deletions (T-ALL). These findings support the use of outlier isoform analysis as a robust strategy for detecting clinically significant DNA events.

P2, N=9, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jul 2023 --> Jul 2024 | Trial primary completion date: Jul 2023 --> Jul 2024

Collectively, we dissected the molecular spectrum and clinical features of IKZF1-related AML, which may promote an in-depth understanding of the pathogenesis, lineage susceptibility and clinical research of AML.

Our results suggest that acute leukemias with complex karyotype show a similarly poor outcome regardless of lineage differentiation and that mutation in TP53 confers a poor prognosis in all lineages. Our results support the exclusion of immunophenotypic MPAL with CK from MPAL and appear to confirm the approach proposed in the revised 4th edition WHO to include them as AML with myelodysplasia-related changes and similar myelodysplasia-related AML categories of newer classifications.

Classification of genes curated by the Antibody Deficiencies GCEP (AD-GCEP) Gene Disease MOI Classification AICDA Hyper-IgM syndrome type 2 (AID deficiency) AR Definitive ATM Ataxia telangiectasia (AT) AR Definitive BLNK Agammaglobulinemia 4, autosomal recessive (BLNK-associated agammaglobulinemia) AR Definitive BTK Bruton-type agammaglobulinemia (X-linked agammaglobulinemia) XLR Definitive BTK Isolated growth hormone deficiency type III XLR Disputed CARD11 BENTA (B cell expansion with NFκB and T cell anergy) disease AD Definitive CARD11 Severe combined immunodeficiency due to CARD11 deficiency AR Definitive CARD11 Immunodeficiency 11b with atopic dermatitis (CARD11 + atopic dermatitis) AD Definitive CD19 Immunodeficiency, common variable, 3 (CD19 deficiency) AR Definitive CD79A Agammaglobulinemia 3, autosomal recessive (Ig-alpha deficiency) AR Definitive CD79B Agammaglobulinemia 6, autosomal recessive (Ig-beta deficiency) AR Definitive CR2 Immunodeficiency, common variable, 7 (CD21 deficiency) AR Definitive CTLA4 Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency (CHAI) AD Definitive IGHM Autosomal recessive agammaglobulinemia 1 (Mu-heavy chain deficiency) AR Definitive IKZF1 Pancytopenia due to IKZF1 mutations; IKAROS deficiency AD Definitive IKZF1 Autoimmune disease, IKAROS defect AD Moderate LRBA Combined immunodeficiency due to LRBA deficiency; LATAIE AR Definitive NFKB1 Immunodeficiency, common variable, 12 (NFkB1 deficiency) AD Definitive NFKB2 Immunodeficiency, common variable, 10 (NFkB2 deficiency, DAVID syndrome) AD Definitive PIK3CD Immunodeficiency 14b, autosomal recessive AR Definitive PIK3CD Immunodeficiency 14 (APDS type 1; activated p110-delta syndrome, PASLI disease) AD Definitive PIK3R1 Immunodeficiency 36 (APDS type 2; gain-of-function disease in PI3K regulatory subunits) AD Definitive PIK3R1 Agammaglobulinemia 7, autosomal recessive (p85alpha subunit defect) AR Limited TNFRSF13B Immunodeficiency, common variable, 2 (TACI deficiency) AR Definitive CD40 Hyper-IgM syndrome type 3 (MONDO:0011735), CD40 deficiency AR Definitive TCF3 Autosomal agammaglobulinemia (MONDO:0011096)/(agammaglobulinemia 8B)/AD (agammaglobulinemia 8A) AR Definitive TRNT1 SIFD (sideroblastic anemia, B cell immunodeficiency, periodic fevers and developmental delay) retinitis pigmentosa with erythrocytic microcytosis AR Definitive ICOS Common variable immunodeficiency, ICOS deficiency AR Definitive IL21R Immunodeficiency 56, IL-21R deficiency AR Definitive FNIP1 FNIP1-associated syndrome, FNIP1 deficiency AR Strong SPI1 Agammaglobulinemia 10, PU.1 deficiency AD Strong IGLL1 Agammaglobulinemia 2, autosomal recessive, Ig light chain deficiency (lambda-like) AR Moderate RAC2 Immunodeficiency 73b with defective neutrophil chemotaxis and lymphopenia, Rac2 deficiency (loss-of-function, LOF) and Rac2 gain-of-function (GOF) AD Strong RAC2 I mmunodeficiency 73c with defective neutrophil chemotaxis and hypogammaglobulinemia, Rac2 deficiency (loss-of-function, LOF) and Rac2 gain-of-function (GOF) AR Moderate RAC2 Neutrophil immunodeficiency syndrome, Rac2 deficiency (loss-of-function, LOF) and Rac2 gain-of-function (GOF) AD Moderate SEC61A1 SEC61A1 deficiency, plasma cell deficiency AD Moderate SLC39A7 Agammaglobulinemia 9, ZIP7 deficiency AR Moderate TOP2B B-cell immunodeficiency, distal limb anomalies, and urogenital malformations, Hoffman syndrome AD Moderate UNG Hyper-IgM syndrome type 5, UNG deficiency AR Moderate ARHGEF1 Immunodeficiency 62, ARHGEF1 deficiency AR Limited CD81 Immunodeficiency, common variable, 6, CD81 deficiency AR Limited CTNNBL1 Common variable immunodeficiency, immunodeficiency 99 with hypogammaglobulinemia and autoimmune cytopenias AR Limited IGKC Recurrent infections associated with rare immunoglobulin isotypes deficiency, Ig kappa light chain deficiency AR Limited IRF2BP2 Immunodeficiency, common variable, 14, IRF2BP2 deficiency AD Limited MS4A1 Immunodeficiency, common variable, 5, CD20 deficiency AR Limited POU2AF1 Agammaglobulinemia, Bob1 deficiency AR Limited SH3KBP1 Immunodeficiency 61, CIN85 deficiency XLR Limited TNFRSF13C Immunodeficiency, common variable, 4, BAFF-R deficiency AR Limited TNFSF12 Common variable immunodeficiency, TWEAK deficiency AD Limited TNFSF13 Common variable immunodeficiency, APRIL deficiency AR Limited IL21 Common variable immunodeficiency 11, IL-21 deficiency AR Limited INO80 immunodeficiency, common variable, 1, INO80 deficiency AR Disputed AR: autosomal recessive; AD: autosomal dominant; XLR: X-linked recessive Table 3 . Genes associated with antibody deficiencies curated in collaboration with other GCEPs Gene Disease Inheritance Collaborating GCEP Classification MOGS MOGS-congenital disorder of glycosylation AR General Inborn Errors of Metabolism GCEP Definitive ATP6AP1 Congenital disorder of glycosylation type II XLR General Inborn Errors of Metabolism GCEP Limited CD40L X-linked Hyper IgM syndrome XLR SCID-CID Definitive KMT2A Wiedemann-Steiner syndrome AD Syndromic Disorders GCEP Definitive MSH6 mismatch repair cancer syndrome 1 AR Hereditary Cancer GCEP Definitive GATA2 Mono-MAC syndrome, Familial myeloid leukemia, DCML deficiency, GATA2 haploinsufficiency AD Hereditary Cancer Definitive PMS2 Mismatch repair cancer syndrome 1 AR Hereditary Cancer Definitive BLK Monogenic diabetes AD Monogenic Diabetes Refuted BRWD1 Primary Ciliary Dyskinesia (PCD) AR Motile Ciliopathy Refuted BRWD1 Agammaglobulinemia, B cell deficiency AD Transferred to AD-GCEP Limited

It was classified as early T-precursor lymphoblastic leukemia/lymphoma and T-ALL, NOS in the WHO revised 4th edition and WHO 5th edition. The ICC added an entity into early T-cell precursor ALL, BCL11B-activated, and also added provisional entities subclassified based on transcription factor families that are aberrantly activated.

This case highlights genetic mutations in a patient with TAM without DS and shows the necessity of performing NGS on unclear cases. Mutations of KRAS are associated with childhood leukemia. Mutations of IKZF1 can cause abnormalities of GATA1 expression in fetal megakaryocytes and thus alter the GATA1 mediated regulation of other transcription factors, ultimately leading to hematopoietic malignancy.

In subgroup analysis, our results showed that IKZF1 mutation conferred poor therapeutic response and prognosis for SF3B1-mutated AML (P = 0.0017). We believe this work improves our knowledge of IKZF1 mutation.

PI3K/mTOR dual inhibition, PI3Kalpha inhibitor, AKT inhibitor, FGFR inhibitor, ALK/IGF1R inhibitor, CDK4/6 inhibitor, BCl2 inhibitor, WEE1 inhibitor, ATR inhibitor, DNA-PK inhibitor, AT2AR inhibitor, Mcl-1 inhibitor, MEK1/2 inhibitor, EZH2 inhibitor, HDAC inhibitor, CDK9 inhibitor, DNMT3 inhibitor, BRD4/BET inhibitor, JAK2 inhibitor, CXCR4 inhibitor, FAK inhibitor, BTK inhibitor, eribulin, & VEGFR2/ PDGFR/FGFR or VEGFR2/c-MET/Axl triple blockage might be effective on TW2.6 and reverse treatment refractoriness, maybe through the inhibition of mesenchymal transformation, pRB, & PI3K/AKT /mTOR signaling and the modulation of stemness & PD1/PDL1 pathway...All cell lines will be tried to be categorized as TCGA subtypes for the reference of future drug combinations.Cell linesSCC25KBSASCAL27FaDuSCC15SCC9SCC4TW2.6Differ- entiationWellPoorPoorPoorPoorWellWellWellWell, but rapidly replicated, with high hyper-diploidy & complex rearrangementsHPV statusHPV 16/18HPV18--HPV 16/18--HPV 6/11-EGFR statusMediumLowHighHighMediumHighLowMedium to highUnknownDocetaxel sensitivity+++++++++++++ to +++++-+Cisplatin sensitivity+++++++++++++- to +-- to +5-FU sensitivity+++++++++++-+ to ++-- to +Afatinib sensitivity+++- to +-+++++ to +++++++++-Polo-like kinase Inhibitor sensitivity+++++++++++++ to +++- to +-- to +VEGFR2 Inhibitor sensitivity----+++++--++PI3K/ mTOR inhibitorAll cell lines sensitiveCDK4/6 Inhibitor response+++- to ++++++ to +++++++++++++ to +++Western blotsWeak p-AKT & VEGF-A, mild PDL1 and BMI-1, Gli-1(+)Weak p-AKT, mild PDL1 and strong VEGF-A & BMI-1, p16(+)Moderate p-AKT & BMI-1, high PDL1, mild VEGF-AHigh p-AKT & VEGF-A, mild PDL1 & BMI-1High VEGF-A, moderate p-AKT & PDL1, weak BMI-1, Gli-1(+)Weak p-AKT & VEGF-A, mild PDL1 & BMI-1Weak p-AKT, VEGF-A, & BMI-1, moderate PDL1Moderate p-AKT & VEGF-A, strong BMI-1, mild PDL1, Gli-1(+)High p-AKT, PDL1, & VEGF-A and moderate BMI-1NGSCCND1 gain, CDKN2A deletion, FRG1 mutation, HGF mutation, p53 mutation, ATR mutation, SMO mutation, RUNX1T1 mutationSTK11 mutation, PDGFRA mutation, IGF1 mutation, BCOR mutation, EGFR mutation, NOTCH1 mutation, MET mutation, IKZF1 mutation, NFKB1 mutation, DPYD mutation, FGFR4 mutation, BRCA1 mutation, MSH2 mutation, DNMT3A mutationKRAS mutation, MDM2 mutation, TMB-H, AXIN1 loss, RAD51D mutation, NOTCH1/2 mutation, ERBB4 mutation, PALB2 mutation, p53 mutation, POLE mutation, CASP8 mutation, BRCA2 mutation, RNF43 mutation, LRP1B mutation, MET mutationCDKN2A deletion, EGFR amplification, SMAD4 mutation, TMB-H, LRP1B mutation, APC mutation, CASP8 mutation, CREBBP mutation, PIK3CG mutation, NRAS mutation, ABL1 mutation, FGF23 mutation, HGF mutation, ATRX mutation, p53 mutation, ERBB2 mutation, ROS1 mutation, EP300 mutation, NRAS mutation, CDKN1A mutation, KDM6A mutation, FLT4 mutationCCND1 gain, CDKN2A deletion, FLCN mutation, TMB-H, LRP1B mutation, SMAD4 loss, SF3B1 mutation, FAT1 mutation, VHL mutation, NOTCH3 mutation, EPHA5 mutation, p53 mutation, ERCC2 mutationCCND1 gain, EGFR amplification, SMO mutation, ATR mutation, FAT1 loss, NTRK1 mutation, KMT2D mutation, p53 mutation, NOTCH3 mutationCDKN2A deletion, AXIN2 amplification, SMAD3 loss, HRAS mutation, ATR mutation, NF1 mutation. IGF1R mutation, FLCN mutation, KEAP1 mutation, ASXL1 mutation, PMS2 mutationCCND1 gain, NF1 loss, LRP1B mutation, NSD1 mutation, KMT2D mutation, p53 mutation, EPHA2 mutationFAT1 loss, CCND3/FGF10 amplification, PIK3CA H1047R mutation, STK11 mutation, RICTOR/FLCN amplification, VEGF-A amplification , TSC2 mutation, EPHB1 mutation, MAP2K4 mutation, KDM5A mutation, PDGFRB mutation, SETD2 mutation, RPTOR mutation, APC mutation, DDR2 mutation, ATM mutation, MDM2 mutation, p53 mutation, CDK12 mutation, HRAS mutation, MYC mutation, CDK8 mutation, ARID1B lossOutcomesBest; like TCGA CL (HPV+) subtypeLike TCGA basal subtype, but responded to particular treatments eachBasalBasalLike TCGA mesen-chymal subtype (HPV+)Like TCGA CL(HPV-) subtype, different characters between these 3 cell linesCL(HPV-) subtypeCL(HPV-) subtypeWorse; like TCGA EMT subtype (HPV-)Potential treatmentsAll sensitive maybe; Hedgehog inhibitor , HGF/c-MET inhibitor, and I/O could be tried(1) Taxane, cisplatin, PLKi (2) mTORi (3) IGF1Ri, METi, PDGFRi, FGFRi (4) Epigenetics (5) I/O(1) Taxane, cisplatin, 5-FU, PLKi (2) CDK4/6i (3) I/O (4) DDRi (5) KRASi, METi, HERi (6) p53 reactivator and MDM2/Mcl-1 inhibitor(1) Taxane, cisplatin, 5-FU, PLKi (2) CDK4/6i (3) Mild EGFRi response (4) I/O (5) NRASi, FGFRi, HGF/c-METi/ROS1i/HERi (6) p53 reactivator/DDRi/Epigenetics(1) Cisplatin, 5-FU (2) EGFRi and VEGFR2i (3) Weak to PLKi & CDK4/6i (4) I/O (5) mTORi (6) Ephi (7) DDR/Epigenetics (8) p53 reactivator (9) HIFi(1) Taxane and PLKi (2) EGFRi, VEGFR2i, CDK4/6i (3) NTRKi (4) Hedgehog inhibitor (5) DDRi, epigenetics,& p53 reactivator(1) Taxane &5-FU (2) EGFRi (3) HRASi (4) DDRi/Epigenetics (5) I/O (6) IGF1Ri (7) mTORi(1) EGFRi (2) CDK4/6i (3) I/O (4) Epigenetics (5) Ephi (6) p53 reactivator(1) CDK4/6 inhibitor (2) Multi-targeted VEGFR TKI (3) PI3K/AKT/mTOR inhibitor (4) ICIs combination (5) p53 reactivator/ DDR interventions/Epigenetics (6) Dasatinib, HRASi, EphB1/B4 interventions Further NGS analysis may translate these HNSCC cell lines to represent TCGA subtypes for the reference of future drug combinations, esp... Further NGS analysis may translate these HNSCC cell lines to represent TCGA subtypes for the reference of future drug combinations, esp. immunotherapy, basic/translational research, and animal models. LRP1B will be a potential ICIs efficacy biomarker in HNSCC.

A second allo-HSCT is an effective salvage therapy for patients who relapsed following an allo-HSCT1. CAR-T therapy prior to an allo-HSCT2 can reduce the risk of CIR after transplantation without increasing the risk incidence of acute/chronic GVHD and CMV/EBV viremia.

Each subgroup was associated with distinct prognosis and drug sensitivities, supporting the clinical applicability of this transcriptome-based classification of AML. These molecular subgroups illuminate the complex molecular network of AML, which may promote systematic studies of disease pathogenesis and foster the screening of targeted agents based on omics.

To date, more than 30 heterozygous IKZF1 germline variants have been reported in patients with primary immunodeficiency. Here we review recent discoveries and clinical/immunological characterization of IKAROS-associated disorders that are linked to different mechanisms of action in IKAROS function.

The GIMEMA LAL2317 is a clinical trial designed for newly diagnosed adult B-lineage Ph-negative ALL that includes two cycles of blinatumomab in the consolidation phase...1. Chiaretti S et al., BJH 2018

The combination of venetoclax and dasatinib resulted in a significant reduction in viability of the SUP-B15 cell line, p185-IK6 mouse leukemia cells, and all 4 samples tested via xenograft as compared to vehicle or either drug. In vivo treatment with venetoclax/dasatinib significantly prolonged survival in the syngeneic mouse model of Ph+ ALL and reduced engraftment in our xenograft model (Figure 1a) compared to vehicle or either drug alone. Secondary transplant of leukemia cells from combination-treated mice failed to engraft in recipient NSG-S mice (Figure 1a).

In summary, our in vivo CRISPR loss-of-function screening enables high-throughput evaluation of the tumorigenic potential of many genetic abnormalities, their cooperability and association with lineage in lymphoid malignancies. Such approach accelerates understanding of genotype-phenotype association and discovery of potential therapeutic targets.

Our findings establish a potential regulatory circuit between the tumor-suppressor Ikaros and the oncogenic miRNA networks in IKZF1-mutated B-ALL. These results indicate that Ikaros regulates the expression of a subset of miRNAs, of which several may contribute to B-ALL growth.

Clinical molecular testing in our cohort revealed these gene alterations mainly in pediatric patients and enabled diagnosis, prognosis, and risk stratification allowing the use of clinically actionable therapeutic targets in some cases. It also contributed toward a useful data set for further analysis and potential for novel drug development. Longer-term followup incorporating therapy and outcomes information would be valuable.

This model is effective to predict the overall survival of adult ALL. It is a simple and easy-to-use model that could efficiently predict the prognosis of adult ALL and is useful for decision making of treatment.

Furthermore, the prognostic panel of IKZF1/CD20 was confirmed in the TARGET cohort. Notably, neither the IKZF1, CD20, or IKZF1/CD20 groups were identified to have poor outcomes in the cohort of allogeneic hematopoietic stem cell transplantation (n = 81).Collectively, our data define IKZF1/CD20 as a very high-risk subtype in B-ALL, and allo-HSCT could abrogate the poor outcome of both IKZF1 and IKZF1/CD20 subsets.

Ruxolitinib as a treatment for RASopathy did not improve eye conditions, whereas systemic lesions were resolved in one patient...In conclusion, a detailed description may pave the way for the CBL mutation ocular phenotype. Genetic analysis using whole-exome sequencing could be useful in the diagnosis of unusual clinical features.

Treatment of B-ALL cells with a specific CK2 inhibitors, CX-4945, resulted in increased Ikaros binding at the RAB21 promoter and reduced RAB21 expression...Together, these data demonstrate that Ikaros and CK2 regulate transcription and overall expression of RAB21 in B-cell ALL. Results uncovered an interplay between CK2 and Rab GTPase signaling pathways and suggest a mechanism by which CK2 regulates Rab21 activity in leukemia.

On the 15th day of induction, minimal residual disease (MRD) > 10 level were higher in IKZF1 mutant patients than wild-type patients (45.5% vs. 22.3%, p = 0.018). In conclusion, our study reveals the association between genetic mutations and clinical features in Chinese children with B-ALL, which might contribute to molecular classification, risk stratification and prognosis evaluation, and provide new ideas for targeted therapy in ALL.

As predicted, birds infected with MDV expressing the mutant Ikaros allele had high tumor incidences (~90%), while there were only a few minute tumors (~12%) produced in birds infected with the virus expressing wild-type Ikaros. Thus, in addition to Meq, key somatic mutations in Ikaros or other potential cancer driver genes in the chicken genome are necessary for MDV to induce lymphomas.

The human immunophenotype was recapitulated in a murine model carrying the corresponding human mutation. As demonstrated here, AIOLOS plays a key role in T and B cell development in humans, and the particular gene variant described is strongly associated with immunodeficiency and likely malignancy.