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Developmental biology - Gene Function|
Some children predisposed to develop leukemia
IKZF1 frequently mutated in leukemic cells.
The discovery comes a decade after Mullighan and his colleagues reported that IKZF1 was frequently mutated in leukemic cells and a harbinger of poor treatment outcomes.
The search for germline IKZF1 variants associated with ALL susceptibility began in Singapore. Nichols and Yang were there to talk about germline genetics of ALL and inherited (familial) cancer. During that visit, co-author Rupert Handgretinger, M.D., of Children's University Hospital, Tuebingen, Germany, mentioned three generations of a German family with a germline variation in IKZF1 and a family history of B-ALL. Two of the five family members with the variant had developed pediatric ALL and died. The remaining three are apparently healthy despite having reduced numbers of B cells.
Targeted sequencing of IKZF1 in 4,963 children with ALL identified 43 patients with 27 IKZF1 variants, almost exclusively patients with B-ALL. "The pattern of IKZF1 variants was surprising because many of the variants were in regions of the gene that are rarely mutated in leukemic cells; these regions of the gene have not been well characterized," Yang said.
IKZF1 variants affect IKAROS function.
Extensive laboratory testing found at least 22 of the 28 variants affected protein functions. For example, IKZF1 variants resulted in IKAROS migrating outside the nucleus, which is where the protein normally functions. In other cases, variants were associated with increased cell adhesion.
"Based on existing models, we would have predicted only 60 percent of the newly identified IKZF1 variants would be deleterious," says Michelle Churchman PhD, of St. Jude Pathology. Churchman and Maoxiang Qian PhD, of St. Jude Pharmaceutical Sciences, and Geertruy te Kronnie, of the University of Padova, Italy, are first authors of the paper.
But, a second variant "hit" causes cancer.
"In IKZF1 and the other ALL predisposition genes, cells may require an additional cooperating mutation to develop into leukemia," Mullighan adds. "While familial ALL is rare, these cases can point to genes and novel biology to examine in a larger patient population. This study demonstrates the power of sequencing large groups of seemingly sporadic cases that reveal the genetic underpinnings of the disease."
• Germline coding IKZF1 variants are present in familial and sporadic B-precursor ALL
• Most variants affect regions outside of known domains and perturb IKAROS function
• Germline IKZF1 variants result in aberrant adhesion and bone marrow mislocalization
• Germline IKZF1 variants result in reduced antileukemic drug sensitivity
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.
The study's other authors include Wenjian Yang, Paige Tedrick, Rebekah Baskin, Katherine Verbist, Jennifer Peters, Ian Moore, Zhaohui Gu, Chunxu Qu, Hiroki Yoshihara, Shaina Porter, Shondra Pruett-Miller, Gang Wu, William Evans, Mary Relling and Ching-Hon Pui, all of St. Jude; Hui Zhang of St. Jude and Guangzhou Women and Children's Medical Center, China; and researchers at 12 institutions in the U.S., China and Germany. The patients in this analysis were enrolled in clinical research conducted by St. Jude and the Children's Oncology Group, a cooperative clinical research network.
The study was funded in part by the St. Baldrick's Foundation, grants (GM115279, CA021765, CA176063, CA19769501A1, CA98543, CA114766, CA98413, CA180886, CA180899) from the National Institutes of Health; and ALSAC, the fundraising and awareness organization of St. Jude.
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Genetic alterations of IKZF1 gene, which encodes the lymphoid factor IKAROS, are common in high-risk acute lymphoblastic leukemia (ALL) associated with a poor prognosis for the child. Image credit: Charles G. Mullighan MD, Department of Pathology, St. Jude Children's Research Hospital.