Germline Genetic IKZF1 Variation and Predisposition to Childhood Acute Lymphoblastic Leukemia

Michelle L. Churchman, Maoxiang Qian, Geertruy te Kronnie, Ranran Zhang, Wenjian Yang, Hui Zhang, Tobia Lana, Paige Tedrick, Rebekah Baskin, Katherine Verbist, Jennifer L. Peters, Meenakshi Devidas, Eric Larsen, Ian M. Moore, Zhaohui Gu, Chunxu Qu, Hiroki Yoshihara, Shaina N. Porter, Shondra M. Pruett-Miller, Gang WuElizabeth Raetz, Paul L. Martin, W. Paul Bowman, Naomi Winick, Elaine Mardis, Robert Fulton, Martin Stanulla, William E. Evans, Mary V. Relling, Ching Hon Pui, Stephen P. Hunger, Mignon L. Loh, Rupert Handgretinger, Kim E. Nichols, Jun J. Yang, Charles G. Mullighan

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Somatic genetic alterations of IKZF1, which encodes the lymphoid transcription factor IKAROS, are common in high-risk B-progenitor acute lymphoblastic leukemia (ALL) and are associated with poor prognosis. Such alterations result in the acquisition of stem cell-like features, overexpression of adhesion molecules causing aberrant cell-cell and cell-stroma interaction, and decreased sensitivity to tyrosine kinase inhibitors. Here we report coding germline IKZF1 variation in familial childhood ALL and 0.9% of presumed sporadic B-ALL, identifying 28 unique variants in 45 children. The majority of variants adversely affected IKZF1 function and drug responsiveness of leukemic cells. These results identify IKZF1 as a leukemia predisposition gene, and emphasize the importance of germline genetic variation in the development of both familial and sporadic ALL. Churchman et al. identify 28 unique germline IKZF1 coding variants in 45 children with acute lymphoblastic leukemia. Many of these variants are not predicted to be damaging using in silico prediction tools, but functional tests reveal that the majority of them have deleterious effects on IKAROS function.

Original languageEnglish
Pages (from-to)937-948.e8
JournalCancer Cell
Volume33
Issue number5
DOIs
StatePublished - 14 May 2018

Fingerprint

Genetic Predisposition to Disease
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Cell Communication
Computer Simulation
Protein-Tyrosine Kinases
Leukemia
Transcription Factors
Stem Cells
Pharmaceutical Preparations
Genes

Keywords

  • ALL
  • IKAROS
  • IKZF1
  • acute lymphoblastic leukemia
  • drug response
  • familial leukemia
  • germline genetic variation
  • immunodeficiency
  • predisposition

Cite this

Churchman, M. L., Qian, M., te Kronnie, G., Zhang, R., Yang, W., Zhang, H., ... Mullighan, C. G. (2018). Germline Genetic IKZF1 Variation and Predisposition to Childhood Acute Lymphoblastic Leukemia. Cancer Cell, 33(5), 937-948.e8. https://doi.org/10.1016/j.ccell.2018.03.021
Churchman, Michelle L. ; Qian, Maoxiang ; te Kronnie, Geertruy ; Zhang, Ranran ; Yang, Wenjian ; Zhang, Hui ; Lana, Tobia ; Tedrick, Paige ; Baskin, Rebekah ; Verbist, Katherine ; Peters, Jennifer L. ; Devidas, Meenakshi ; Larsen, Eric ; Moore, Ian M. ; Gu, Zhaohui ; Qu, Chunxu ; Yoshihara, Hiroki ; Porter, Shaina N. ; Pruett-Miller, Shondra M. ; Wu, Gang ; Raetz, Elizabeth ; Martin, Paul L. ; Bowman, W. Paul ; Winick, Naomi ; Mardis, Elaine ; Fulton, Robert ; Stanulla, Martin ; Evans, William E. ; Relling, Mary V. ; Pui, Ching Hon ; Hunger, Stephen P. ; Loh, Mignon L. ; Handgretinger, Rupert ; Nichols, Kim E. ; Yang, Jun J. ; Mullighan, Charles G. / Germline Genetic IKZF1 Variation and Predisposition to Childhood Acute Lymphoblastic Leukemia. In: Cancer Cell. 2018 ; Vol. 33, No. 5. pp. 937-948.e8.
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abstract = "Somatic genetic alterations of IKZF1, which encodes the lymphoid transcription factor IKAROS, are common in high-risk B-progenitor acute lymphoblastic leukemia (ALL) and are associated with poor prognosis. Such alterations result in the acquisition of stem cell-like features, overexpression of adhesion molecules causing aberrant cell-cell and cell-stroma interaction, and decreased sensitivity to tyrosine kinase inhibitors. Here we report coding germline IKZF1 variation in familial childhood ALL and 0.9{\%} of presumed sporadic B-ALL, identifying 28 unique variants in 45 children. The majority of variants adversely affected IKZF1 function and drug responsiveness of leukemic cells. These results identify IKZF1 as a leukemia predisposition gene, and emphasize the importance of germline genetic variation in the development of both familial and sporadic ALL. Churchman et al. identify 28 unique germline IKZF1 coding variants in 45 children with acute lymphoblastic leukemia. Many of these variants are not predicted to be damaging using in silico prediction tools, but functional tests reveal that the majority of them have deleterious effects on IKAROS function.",
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Churchman, ML, Qian, M, te Kronnie, G, Zhang, R, Yang, W, Zhang, H, Lana, T, Tedrick, P, Baskin, R, Verbist, K, Peters, JL, Devidas, M, Larsen, E, Moore, IM, Gu, Z, Qu, C, Yoshihara, H, Porter, SN, Pruett-Miller, SM, Wu, G, Raetz, E, Martin, PL, Bowman, WP, Winick, N, Mardis, E, Fulton, R, Stanulla, M, Evans, WE, Relling, MV, Pui, CH, Hunger, SP, Loh, ML, Handgretinger, R, Nichols, KE, Yang, JJ & Mullighan, CG 2018, 'Germline Genetic IKZF1 Variation and Predisposition to Childhood Acute Lymphoblastic Leukemia', Cancer Cell, vol. 33, no. 5, pp. 937-948.e8. https://doi.org/10.1016/j.ccell.2018.03.021

Germline Genetic IKZF1 Variation and Predisposition to Childhood Acute Lymphoblastic Leukemia. / Churchman, Michelle L.; Qian, Maoxiang; te Kronnie, Geertruy; Zhang, Ranran; Yang, Wenjian; Zhang, Hui; Lana, Tobia; Tedrick, Paige; Baskin, Rebekah; Verbist, Katherine; Peters, Jennifer L.; Devidas, Meenakshi; Larsen, Eric; Moore, Ian M.; Gu, Zhaohui; Qu, Chunxu; Yoshihara, Hiroki; Porter, Shaina N.; Pruett-Miller, Shondra M.; Wu, Gang; Raetz, Elizabeth; Martin, Paul L.; Bowman, W. Paul; Winick, Naomi; Mardis, Elaine; Fulton, Robert; Stanulla, Martin; Evans, William E.; Relling, Mary V.; Pui, Ching Hon; Hunger, Stephen P.; Loh, Mignon L.; Handgretinger, Rupert; Nichols, Kim E.; Yang, Jun J.; Mullighan, Charles G.

In: Cancer Cell, Vol. 33, No. 5, 14.05.2018, p. 937-948.e8.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Germline Genetic IKZF1 Variation and Predisposition to Childhood Acute Lymphoblastic Leukemia

AU - Churchman, Michelle L.

AU - Qian, Maoxiang

AU - te Kronnie, Geertruy

AU - Zhang, Ranran

AU - Yang, Wenjian

AU - Zhang, Hui

AU - Lana, Tobia

AU - Tedrick, Paige

AU - Baskin, Rebekah

AU - Verbist, Katherine

AU - Peters, Jennifer L.

AU - Devidas, Meenakshi

AU - Larsen, Eric

AU - Moore, Ian M.

AU - Gu, Zhaohui

AU - Qu, Chunxu

AU - Yoshihara, Hiroki

AU - Porter, Shaina N.

AU - Pruett-Miller, Shondra M.

AU - Wu, Gang

AU - Raetz, Elizabeth

AU - Martin, Paul L.

AU - Bowman, W. Paul

AU - Winick, Naomi

AU - Mardis, Elaine

AU - Fulton, Robert

AU - Stanulla, Martin

AU - Evans, William E.

AU - Relling, Mary V.

AU - Pui, Ching Hon

AU - Hunger, Stephen P.

AU - Loh, Mignon L.

AU - Handgretinger, Rupert

AU - Nichols, Kim E.

AU - Yang, Jun J.

AU - Mullighan, Charles G.

PY - 2018/5/14

Y1 - 2018/5/14

N2 - Somatic genetic alterations of IKZF1, which encodes the lymphoid transcription factor IKAROS, are common in high-risk B-progenitor acute lymphoblastic leukemia (ALL) and are associated with poor prognosis. Such alterations result in the acquisition of stem cell-like features, overexpression of adhesion molecules causing aberrant cell-cell and cell-stroma interaction, and decreased sensitivity to tyrosine kinase inhibitors. Here we report coding germline IKZF1 variation in familial childhood ALL and 0.9% of presumed sporadic B-ALL, identifying 28 unique variants in 45 children. The majority of variants adversely affected IKZF1 function and drug responsiveness of leukemic cells. These results identify IKZF1 as a leukemia predisposition gene, and emphasize the importance of germline genetic variation in the development of both familial and sporadic ALL. Churchman et al. identify 28 unique germline IKZF1 coding variants in 45 children with acute lymphoblastic leukemia. Many of these variants are not predicted to be damaging using in silico prediction tools, but functional tests reveal that the majority of them have deleterious effects on IKAROS function.

AB - Somatic genetic alterations of IKZF1, which encodes the lymphoid transcription factor IKAROS, are common in high-risk B-progenitor acute lymphoblastic leukemia (ALL) and are associated with poor prognosis. Such alterations result in the acquisition of stem cell-like features, overexpression of adhesion molecules causing aberrant cell-cell and cell-stroma interaction, and decreased sensitivity to tyrosine kinase inhibitors. Here we report coding germline IKZF1 variation in familial childhood ALL and 0.9% of presumed sporadic B-ALL, identifying 28 unique variants in 45 children. The majority of variants adversely affected IKZF1 function and drug responsiveness of leukemic cells. These results identify IKZF1 as a leukemia predisposition gene, and emphasize the importance of germline genetic variation in the development of both familial and sporadic ALL. Churchman et al. identify 28 unique germline IKZF1 coding variants in 45 children with acute lymphoblastic leukemia. Many of these variants are not predicted to be damaging using in silico prediction tools, but functional tests reveal that the majority of them have deleterious effects on IKAROS function.

KW - ALL

KW - IKAROS

KW - IKZF1

KW - acute lymphoblastic leukemia

KW - drug response

KW - familial leukemia

KW - germline genetic variation

KW - immunodeficiency

KW - predisposition

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U2 - 10.1016/j.ccell.2018.03.021

DO - 10.1016/j.ccell.2018.03.021

M3 - Article

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VL - 33

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JO - Cancer Cell

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Churchman ML, Qian M, te Kronnie G, Zhang R, Yang W, Zhang H et al. Germline Genetic IKZF1 Variation and Predisposition to Childhood Acute Lymphoblastic Leukemia. Cancer Cell. 2018 May 14;33(5):937-948.e8. https://doi.org/10.1016/j.ccell.2018.03.021