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Acute Lymphoblastic Leukaemia
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
Several genetic BCP-ALL subtypes with no single defining chromosomal alteration have been recognized in about 25% childhood and a higher proportion of adults. These include the Ph-like (BCR-ABL1-like), which has a similar gene expression profile as BCR-ABL1-positive ALL, but do not have BCR-ABL1 and are recognized in the 2016 WHO classification. Genome-wide approaches have also demonstrated a high frequency of IKZF1, a gene that encodes the lymphoid transcription factor IKAROS, and PAX5 deletions. Multivariate analysis confirms the very poor prognosis conferred by any genetic alteration of IKZF1 and the unfavourable response to current standard therapy.
B-Lymphoblastic Leukemia/Lymphoma
Published in Wojciech Gorczyca, Atlas of Differential Diagnosis in Neoplastic Hematopathology, 2014
IKZF1 deletions (and sequence mutations) occur in ~15% of childhood ALLs and are associated with high-risk disease and treatment resistance. IKZF1 encodes IKAROS, the member of a family of zinc finger transcription factors that are required for the development of all lymphoid lineages. The IKZF1 alterations observed in ALL include focal or broad deletions that result in loss of function and internal deletions of coding exons 4–7. IKZF1 alterations are present in >70% of BCR–ABL1+ ALLs, including de novo ALL and chronic myeloid leukemia at progression to lymphoid blast crisis [59]. IKZF1-mutated cases exhibit a gene expression profile similar to BCR–ABL1+ ALL and harbor novel kinase-activating mutations and rearrangements.
Leukaemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2014
In B-ALL/B-LBL, the various cytogenetic abnormalities can conveniently be divided into two groups: those with numerical chromosomal abnormnalities; hypodiploidy, high hyperdiploidy with either less than 40 chromoosmes or more than 50 chromosomes, respectively, and those with structural chromosomal abnormalities including translocations. High hyperdiploidy (51–65 chromosomes) is found in up to 30% of children and 10% of adults with ALL and is associated with an excellent prognosis because the lymphoblasts demonstrate unique susceptibility to anti-metabolites.61 The observation that about half of these patients develop additional cytogenetic abnormalities, in particular duplications of chromosome 1q and isochromosome of 17q, has led to the hypothesis of a probable ‘two-hit’ genetic event resulting in a transformed phenotype that may not respond to therapy as well. Approximately 25%–30% of adults and 3% of children have a Philadelphia (Ph) chromosome [t(9;22)(q34;q11)]. One-third of Ph-positive ALL patients have BCR-ABL1 transcripts indistinguishable from those found in CML. The remaining two-thirds have a breakpoint in the first intron of the BCR1 gene (between e1 and e2) in an area designated the minor breakpoint cluster region (m-bcr); this is transcribed as an e1a2 mRNA, which encodes a 190 kD protein (p190BCR-ABL1), in contrast to the p210BCR-ABL1 typical of CML.62 Genomewide approaches have demonstrated a high frequency of IKZF1, a gene that encodes the lymphoid transcription factor IKAROS, and PAX5 deletions, of which IKZF1 deletions portend a poor prognosis.63 Multivariate analysis confirms the very poor prognosis conferred by any genetic alteration of IKZF1 and the unfavourable response to current standard therapy.64 A recently recognized genetic subtype, known as ‘BCR-ABL1-like’, shows a similar gene expression signature to BCR-ABL1-positive ALL and shares the same poor-risk features. Uniquely, this is associated with a high incidence of IKZF1 deletions, deregulated CRLF2 and JAK mutations.
Quantitative analysis of IKZF1 gene deletions in pediatric B-cell precursor acute lymphoblastic leukemia: higher levels are associated with a poorer prognosis
Published in Pediatric Hematology and Oncology, 2022
Zhizhuo Huang, Yueping Jia, Guorui Ruan, Yingxi Zuo, Jun Wu, Aidong Lu, Yujuan Xue, Yifei Cheng, Leping Zhang
The IKZF1 gene is located on chromosome 7p12 and encodes the lymphoid transcription protein Ikaros, which plays a key regulatory role in lymphopoiesis.2 Deletion or mutation of the IKZF1 gene is the hallmark of both BCR–ABL1-positive ALL and Ph-like ALL patients. In most cases, IKZF1 gene deletion has been recognized as a poor prognostic factor in pediatric ALL.3 Most data on IKZF1 deletions in pediatric ALL have been obtained through multiplex ligation probe-dependent amplification (MLPA) analyses, single nucleotide polymorphism (SNP) arrays, or polymerase chain reaction (PCR) assays, which cannot be used to detect minimal residual disease (MRD) in ALL. Recently, the levels of the IKZF1 Δ2-8/albumin (ALB) gene deletion have been detected using a real-time quantitative polymerase chain reaction (RT-PCR) and used to monitor MRD in ALL. In this study, a quantitative analysis of IKZF1 gene deletion was conducted in pediatric patients with BCP–ALL to explore the relationship between different levels of IKZF1 gene deletions and prognosis.
Primary Immunodeficiency and Thrombocytopenia
Published in International Reviews of Immunology, 2022
Maryam Mohtashami, Azadehsadat Razavi, Hassan Abolhassani, Asghar Aghamohammadi, Reza Yazdani
IKAROS is a zinc-finger transcription factor that is not only expressed in all HSCs, but also acts as a key component in the early stages of B- cell development, specification and its commitment. IKAROS structure contains two parts. The first part is characterized by the N-terminal DNA-binding motif and C2H2 zinc-finger domain locating in this area. The latter part is C-terminal, which is responsible for Ikaros family members and connecting via two zinc-finger domains. Two C-terminal zinc-finger domains are recruited for homologous or heterogeneous dimers formation and four germlines heterozygous IKAROS variants affect this region via haploinsuffiency [118, 119]. IKZF1 gene encodes the transcription factor IKAROS. This molecule acts as a regulator of B- cell differentiation [120]. Mutation in the IKZF1 gene leads to B- cell deficiency. In addition to B-cell deficiency, malignancy progressions such as hematological malignancies (leukemia) and solid tumors are accompanied by IKAROS mutation. The lack of IKAROS, for instance, is associated with downregulation of IL-7 receptor on naïve T cell surface or reduction of B cell progenitors in the bone marrow [118, 119]. Studies have highlighted the importance of IKAROS deficiency in boosting megakaryocyte production. However, S. Malinge supposed that IKZF5 is associated with mild thrombocytopenia and there is still no evidence to establish whether IKZF1 involve in platelet development [64, 120–122].
Germline IKZF1 mutations and their impact on immunity: IKAROS-associated diseases and pathophysiology
Published in Expert Review of Clinical Immunology, 2021
Hye Sun Kuehn, Cristiane J Nunes-Santos, Sergio D. Rosenzweig
Based on the experience gained from more than 90 PID/IEI published patients carrying IKZF1 germline heterozygous mutations, the role of IKAROS in human immunity of lymphoid and myeloid cells has been extensively demonstrated (Table 1 and Figure 3). The immunological and in its turn clinical phenotype of patients carrying IKZF1 mutations depend on the protein domain primarily affected (i.e., DNA binding or dimerization) and the pathophysiology mechanism involved (i.e., haploinsufficiency or dominant negative). In terms of lineage-specific impact, a reduction of B cell numbers can be detected among the three allelic variants reported so far (severity DN>HI>DD). T cells, on the other hand, are heavily impacted by DN mutations and to a lesser extent by HI and DD mutations, as reflected by their clinical presentations: while T-cell dependent opportunistic infections are the rule in patients with DN variants (i.e., pneumocystis pneumonia), they are extremely rare in the other two allelic variants. Moreover, myeloid involvement is evident in patients with DN, DD and HI variants, through different mechanisms and with different penetrance and expressivity levels. The above-described genotype/phenotype correlation may also represent a gene dosage effect by this transcription factor where ‘stronger’ mutations (i.e., DN) have a more penetrant, immunologically broader and clinically more severe impact, opposed to ‘milder’ variants (e.g., null mutations deleting a full allele but allowing the expression of ~50% of WT IKAROS) presenting with a less penetrant, more limited immune and clinical disease.