Germline Genetic IKZF1 Variation and Predisposition to Childhood Acute Lymphoblastic Leukemia

Churchman, Michelle L.; Qian, Maoxiang; Kronnie, Geertruy te; Zhang, Ranran; Yang, Wenjian; Zhang, Hui; Lana, Tobia; Tedrick, Paige; Baskin, Rebekah; Verbist, Katherine; Peters, Jennifer L.; Devidas, Meenakshi; Raetz, Elizabeth A.; Larsen, Eric; Martin, Paul L.; Bowman, W. Paul; Winick, Naomi J.; Mardis, Elaine R.; Fulton, Robert S.; Stanulla, Martin; Evans, William E.; Relling, Mary V.; Pui, Ching‐Hon; Hunger, Stephen P.; Loh, Mignon L.; Handgretinger, Rupert; Nichols, Kim E.; Mullighan, Charles G.; Yang, Jun J.

doi:10.2139/ssrn.3155671

Cited by 15 publications

(20 citation statements)

References 55 publications

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“…Recent research has identified several germline mutations in genes that play a critical role in hematopoiesis and lymphoid development and that are also frequently somatically mutated in ALL, such as PAX5 194 , 195 , ETV6 196 , 197 , RUNX11 198 , and IKZF1 199 , which align with the findings of high subtype concordance in familial cases of ALL 195 , 197 , 200 , 201 . This indicates that pure familial ALL syndromes may constitute a substantial part of ALL etiology and that more such syndromes are expected to emerge in parallel with a growing number of patients being germline-sequenced and with a deeper understanding of the impact of coding and non-coding DNA interactions 196 .…”

Section: Leukemia Predisposition Syndromessupporting

confidence: 57%

Non-infectious chemotherapy-associated acute toxicities during childhood acute lymphoblastic leukemia therapy

et al. 2017

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During chemotherapy for childhood acute lymphoblastic leukemia, all organs can be affected by severe acute side effects, the most common being opportunistic infections, mucositis, central or peripheral neuropathy (or both), bone toxicities (including osteonecrosis), thromboembolism, sinusoidal obstruction syndrome, endocrinopathies (especially steroid-induced adrenal insufficiency and hyperglycemia), high-dose methotrexate-induced nephrotoxicity, asparaginase-associated hypersensitivity, pancreatitis, and hyperlipidemia. Few of the non-infectious acute toxicities are associated with clinically useful risk factors, and across study groups there has been wide diversity in toxicity definitions, capture strategies, and reporting, thus hampering meaningful comparisons of toxicity incidences for different leukemia protocols. Since treatment of acute lymphoblastic leukemia now yields 5-year overall survival rates above 90%, there is a need for strategies for assessing the burden of toxicities in the overall evaluation of anti-leukemic therapy programs.

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Section: Leukemia Predisposition Syndromessupporting

confidence: 57%

Non-infectious chemotherapy-associated acute toxicities during childhood acute lymphoblastic leukemia therapy

et al. 2017

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“…Including the present study, a total of 53 individuals from 17 families with germline variants in IKZF1 have been published (Mendoza-Londono et al, 2005;Goldman et al, 2012;Kuehn et al, 2016;Hoshino et al, 2017;Yoshida et al, 2017;Churchman et al, 2018). In total, 8 out of 53 (15%) individuals with heterozygous missense or loss-of-function mutations developed childhood ALL, including the two reported here; seven cases of BCP-ALL (Mendoza-Londono et al, 2005;Kuehn et al, 2016;Churchman et al, 2018) and one T-ALL . In addition, 37 overlapping deletions (size range 0Á023-159Á08 Mb) have been reported (DECIPHER, https:// decipher.sanger.ac.uk; ISCA, http://dbsearch.clinicalgenome.…”

mentioning

confidence: 75%

“…None were reported to have developed childhood leukaemia. Recently, Churchman et al (2018) reported a fraction (0Á8%, n = 4963) of sporadic ALL carrying rare germline IKZF1 variants but found no deletions. Thus, IKAROS disruption, including haploinsufficiency, is associated with childhood cancer predisposition.…”

mentioning

confidence: 99%

Microdeletion of 7p12.1p13, including IKZF1, causes intellectual impairment, overgrowth, and susceptibility to leukaemia

Järviaho

Zachariadis²,

Tesi

et al. 2018

Br J Haematol

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“…Point mutations of PAX5 P80R in the DNA binding can affect the ability of PAX5 to bind DNAs and regulate expressions. These mutations represent the first molecular subtype defined on the basis of homogeneous hotspot mutations and gene expression profiles [8,9,65,86,108,109]. Most patients with PAX5 P80R presented distinct gene expression profiles and uniform genetic alterations.…”

Section: Pax5-driven Subtypes: Pax5alt and Pax5 Ppro80argmentioning

confidence: 99%

“…IKZF1, also known as IKAROS, is a critical transcription factor related to the differentiation and maturation of the Bcell precursor. Somatic alterations of IKZF1 are a hallmark of high-risk BCP-ALL with poor response to therapy [72,109,142]. Point mutations of IKZF1 p.Asn159Tyr (N159Y) were recently recognized as a rare subtype (< 1%) in BCP-ALL.…”

Section: Ikzf1 Pasn159tyr (N159y)mentioning

confidence: 99%

Emerging molecular subtypes and therapeutic targets in B-cell precursor acute lymphoblastic leukemia

Dai

et al. 2021

Front. Med.

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B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is characterized by genetic alterations with high heterogeneity. Precise subtypes with distinct genomic and/or gene expression patterns have been recently revealed using high-throughput sequencing technology. Most of these profiles are associated with recurrent non-overlapping rearrangements or hotspot point mutations that are analogous to the established subtypes, such as DUX4 rearrangements, MEF2D rearrangements, ZNF384/ZNF362 rearrangements, NUTM1 rearrangements, BCL2/MYC and/or BCL6 rearrangements, ETV6-RUNX1-like gene expression, PAX5alt (diverse PAX5 alterations, including rearrangements, intragenic amplifications, or mutations), and hotspot mutations PAX5 (p.Pro80Arg) with biallelic PAX5 alterations, IKZF1 (p.Asn159Tyr), and ZEB2 (p.His1038Arg). These molecular subtypes could be classified by gene expression patterns with RNA-seq technology. Refined molecular classification greatly improved the treatment strategy. Multiagent therapy regimens, including target inhibitors (e.g., imatinib), immunomodulators, monoclonal antibodies, and chimeric antigen receptor T-cell (CAR-T) therapy, are transforming the clinical practice from chemotherapy drugs to personalized medicine in the field of risk-directed disease management. We provide an update on our knowledge of emerging molecular subtypes and therapeutic targets in BCP-ALL.

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Germline Genetic IKZF1 Variation and Predisposition to Childhood Acute Lymphoblastic Leukemia

Cited by 15 publications

References 55 publications

Non-infectious chemotherapy-associated acute toxicities during childhood acute lymphoblastic leukemia therapy

Non-infectious chemotherapy-associated acute toxicities during childhood acute lymphoblastic leukemia therapy

Microdeletion of 7p12.1p13, including IKZF1, causes intellectual impairment, overgrowth, and susceptibility to leukaemia

Emerging molecular subtypes and therapeutic targets in B-cell precursor acute lymphoblastic leukemia

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