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Study reveals gene variants that predispose kids to ALL

Research Hospital/Seth Dixon
From left: Charles Mullighan, Michelle Churchman, Max Qian, and Jun Yang Photo from St. Jude Children’s

Germline variants in IKZF1 can predispose carriers to acute lymphoblastic leukemia (ALL), according to a study published in Cancer Cell.

The research began with the discovery of an IKZF1 variant in 3 generations of a German family affected by pediatric ALL.

Researchers then analyzed data from nearly 5000 children with ALL and identified 27 additional germline variants in IKZF1.

These variants were present in 0.9% of the patients analyzed, and most of the patients with the variants had B-cell ALL.

“This finding adds to the growing body of evidence that, while germline variations still account for a small percentage of pediatric ALL cases overall, more children than previously recognized inherit a predisposition to develop ALL,” said Charles Mullighan, MBBS, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

In the Cancer Cell paper, Dr Mullighan and his colleagues report the discovery of a germline deletion variant in IKZF1 (c.del556 or D186fs), which was present in 3 generations of a family.

Two of the 6 family members with this variant had developed B-ALL as children and died. The remaining 4 subjects are apparently healthy, despite having reduced numbers of B cells.

To build upon this discovery, the researchers performed targeted sequencing of IKZF1 in 4963 children with ALL.

This revealed 27 additional IKZF1 variants in 43 patients, most of whom had B-ALL. (One patient had T-cell ALL, and, for 8 patients, their subtype was unknown.)

The researchers noted that the variants were distributed across the gene.

“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,” said study author Jun J. Yang, PhD, of St. Jude. “These regions of the gene have not been well characterized.”

The researchers also found that 22 of the 28 IKZF1 variants adversely affect gene function, while the remaining 6 variants appear to be benign.

The team said the deleterious variants impair DNA binding and regulation of transcriptional targets, induce aberrant leukemic cell adhesion, and reduce ALL cells’ sensitivity to treatment with dasatinib and dexamethasone.

The researchers identified the most deleterious variants as 5 that are located outside of the zinc-finger domains (M31V, M347V, R423C, A434G, and L449F), 2 variants affecting the N-terminal DNA-binding domain (R162P and H163Y), 2 truncating nonsense variants (M306* and C394*), and the frameshift variant discovered in the German family (D186fs).

“This [research] will expand the number of genes to consider when screening for predisposition to leukemia, particularly B-ALL,” said study author Kim Nichols, of St. Jude.

“And while not everyone carrying a germline IKZF1 variant will develop leukemia, these results will help us educate families about the potential risk of leukemia.”

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Research Hospital/Seth Dixon
From left: Charles Mullighan, Michelle Churchman, Max Qian, and Jun Yang Photo from St. Jude Children’s

Germline variants in IKZF1 can predispose carriers to acute lymphoblastic leukemia (ALL), according to a study published in Cancer Cell.

The research began with the discovery of an IKZF1 variant in 3 generations of a German family affected by pediatric ALL.

Researchers then analyzed data from nearly 5000 children with ALL and identified 27 additional germline variants in IKZF1.

These variants were present in 0.9% of the patients analyzed, and most of the patients with the variants had B-cell ALL.

“This finding adds to the growing body of evidence that, while germline variations still account for a small percentage of pediatric ALL cases overall, more children than previously recognized inherit a predisposition to develop ALL,” said Charles Mullighan, MBBS, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

In the Cancer Cell paper, Dr Mullighan and his colleagues report the discovery of a germline deletion variant in IKZF1 (c.del556 or D186fs), which was present in 3 generations of a family.

Two of the 6 family members with this variant had developed B-ALL as children and died. The remaining 4 subjects are apparently healthy, despite having reduced numbers of B cells.

To build upon this discovery, the researchers performed targeted sequencing of IKZF1 in 4963 children with ALL.

This revealed 27 additional IKZF1 variants in 43 patients, most of whom had B-ALL. (One patient had T-cell ALL, and, for 8 patients, their subtype was unknown.)

The researchers noted that the variants were distributed across the gene.

“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,” said study author Jun J. Yang, PhD, of St. Jude. “These regions of the gene have not been well characterized.”

The researchers also found that 22 of the 28 IKZF1 variants adversely affect gene function, while the remaining 6 variants appear to be benign.

The team said the deleterious variants impair DNA binding and regulation of transcriptional targets, induce aberrant leukemic cell adhesion, and reduce ALL cells’ sensitivity to treatment with dasatinib and dexamethasone.

The researchers identified the most deleterious variants as 5 that are located outside of the zinc-finger domains (M31V, M347V, R423C, A434G, and L449F), 2 variants affecting the N-terminal DNA-binding domain (R162P and H163Y), 2 truncating nonsense variants (M306* and C394*), and the frameshift variant discovered in the German family (D186fs).

“This [research] will expand the number of genes to consider when screening for predisposition to leukemia, particularly B-ALL,” said study author Kim Nichols, of St. Jude.

“And while not everyone carrying a germline IKZF1 variant will develop leukemia, these results will help us educate families about the potential risk of leukemia.”

Research Hospital/Seth Dixon
From left: Charles Mullighan, Michelle Churchman, Max Qian, and Jun Yang Photo from St. Jude Children’s

Germline variants in IKZF1 can predispose carriers to acute lymphoblastic leukemia (ALL), according to a study published in Cancer Cell.

The research began with the discovery of an IKZF1 variant in 3 generations of a German family affected by pediatric ALL.

Researchers then analyzed data from nearly 5000 children with ALL and identified 27 additional germline variants in IKZF1.

These variants were present in 0.9% of the patients analyzed, and most of the patients with the variants had B-cell ALL.

“This finding adds to the growing body of evidence that, while germline variations still account for a small percentage of pediatric ALL cases overall, more children than previously recognized inherit a predisposition to develop ALL,” said Charles Mullighan, MBBS, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

In the Cancer Cell paper, Dr Mullighan and his colleagues report the discovery of a germline deletion variant in IKZF1 (c.del556 or D186fs), which was present in 3 generations of a family.

Two of the 6 family members with this variant had developed B-ALL as children and died. The remaining 4 subjects are apparently healthy, despite having reduced numbers of B cells.

To build upon this discovery, the researchers performed targeted sequencing of IKZF1 in 4963 children with ALL.

This revealed 27 additional IKZF1 variants in 43 patients, most of whom had B-ALL. (One patient had T-cell ALL, and, for 8 patients, their subtype was unknown.)

The researchers noted that the variants were distributed across the gene.

“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,” said study author Jun J. Yang, PhD, of St. Jude. “These regions of the gene have not been well characterized.”

The researchers also found that 22 of the 28 IKZF1 variants adversely affect gene function, while the remaining 6 variants appear to be benign.

The team said the deleterious variants impair DNA binding and regulation of transcriptional targets, induce aberrant leukemic cell adhesion, and reduce ALL cells’ sensitivity to treatment with dasatinib and dexamethasone.

The researchers identified the most deleterious variants as 5 that are located outside of the zinc-finger domains (M31V, M347V, R423C, A434G, and L449F), 2 variants affecting the N-terminal DNA-binding domain (R162P and H163Y), 2 truncating nonsense variants (M306* and C394*), and the frameshift variant discovered in the German family (D186fs).

“This [research] will expand the number of genes to consider when screening for predisposition to leukemia, particularly B-ALL,” said study author Kim Nichols, of St. Jude.

“And while not everyone carrying a germline IKZF1 variant will develop leukemia, these results will help us educate families about the potential risk of leukemia.”

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