Increased Incidence of IKZF1 Deletions and IGH-CRLF2 Translocations Observed in Hispanic/Latino Children With B-cell ALL

March 3, 2021
Hannah Slater

In this study, investigators sough to determine the incidence of CRLF2 rearrangements and IKZF1 deletions in Hispanic versus non-Hispanic children with B-cell acute lymphoblastic leukemia.

An editorial published in Leukemia revealed that IGH-CRLF2 translocations and IKZF1 deletions provide a biological basis for the health disparity in pediatric B-cell acute lymphoblastic leukemia (B-cell ALL) for Hispanic/Latino (H/L) children as well as a strong biological rationale for the higher deathrate they experience due to B-cell ALL.1

“Our study suggests that, in addition to reducing socioeconomic inequities, the following changes in clinical practice would improve the prognosis of H/L children with B-ALL: (1) due to the high incidence of IGH-CRLF2 translocation and IKZF1 deletion, every child of H/L background with [B-cell ALL] should be tested specifically for the presence of both of these genetic alterations; and (2) novel treatment strategies that restore IKAROS function while targeting CRLF2 signaling pathways (e.g., JAK/STAT or PI3K/AKT/mTOR), should be developed and clinically tested to reduce the health disparity in pediatric [B-cell ALL],” wrote the study authors, who were led by Gordana Raca, MD, PhD, FACMG.

A prior study of children with high-risk B-cell ALL demonstrated an increased incidence of the CRLF2 gene rearrangement in H/L children versus non-H/L children. Moreover, the CRLF2 gene rearrangement was also found to be associated with deletion of the IKZF1 tumor suppressor.2 Thus, investigators sough to determine the incidence of CRLF2 rearrangement and IKZF1 deletion in H/L versus non-H/L children with B-cell ALL.

In this single-center analysis, investigators assessed clinical and molecular data from 239 pediatric patients with B-cell ALL treated at Children’s Hospital Los Angeles between March 2016 and July 2019. Of the total study cohort, 164 self-reported as H/L and 75 self-reported as non-H/L.

Of note, CRLF2 rearrangements consist of 2 types of genetic alterations, including IGH-CRLF2 translocations and P2RY8-CRLF2 fusions. Separate evaluations of these genetic alterations revealed significantly increased incidence of IGH-CRLF2 translocations in the H/L versus non-H/L populations, at 12% (n = 19) versus 2.7% (n = 2), respectively (P =.026). However, the incidence of P2RY8-CRLF2 fusions was not deemed to be significantly different between the 2 patient groups.

Regarding the incidence of IKZF1 deletion, B-cell ALL among the H/L population demonstrated a significantly higher incidence of the deletion compared with the non-H/L group, at 29% (n = 48) versus 15% (n = 11), respectively (P =.016).

“Thus, these data provide evidence of IGH-CRLF2 translocation and IKZF1 deletion as biological determinants of the health disparity in pediatric [B-cell ALL] for H/L patients and suggest a biological rationale for the inferior outcome of H/L children with this disease,” the authors explained.

The investigators then sought to understand whether the age of patients affects the incidence and/or racial difference of these genetic alterations in B-cell ALL.

Among children who were 10 years of age or older, the incidence of IKZF1 deletions was found to have increased 2.8-fold in the H/L versus non-H/L population, at 59% (35 out of 59) versus 21% (5 out of 24), respectively (OR, 5.4; P =.002). Compared with children less than 10 years of age, IKZF1 deletions were also highly increased among H/L children 10 years of age or older (59% vs 12%), though not in the non-H/L group.

Among children 10 years of age or older, the incidence of IGH-CRLF2 translocations was revealed to be strongly increased among the H/L versus non-H/L population, at 31% (18 out of 59) versus 0% (0 out of 24), respectively (P =.001). The incidence of IGH-CRLF2 translocation was also highly increased in H/L children 10 years of age or older (31%; 18 out of 59) compared with those who were less than 10 years of age (1%; 1 out of 105), though this was again not observed in the non-H/L group.

Notably, all of the patients who were 10 years of age or older with IGH-CRLF2 translocations in both the H/L and non-H/L group also had concomitant IKZF1 deletions. Contrastingly, among those who were 10 years of age or older, the IKZF1 deletion without the presence of the IGH-CRLF2 translocations was detected in 17 of the 19 children (29%) in the H/L population.

Of those who were less than 10 years of age, neither IGH-CRLF2 translocation, IKZF1 deletion, nor the combination of the 2 alterations were revealed to have a significant difference in incidence between the H/L and non-H/L populations.

“The results of our study lead to two main questions: (1) What biological factors cause increased incidence of IKZF1 deletion in H/L children; and (2) Does the presence of IKZF1 deletion in the B-lineage make cells more susceptible to the IGH-CRLF2 translocation, and if so, why is that susceptibility stronger in H/L children than in non-H/L populations,” noted the authors. “Answering these questions will help in understanding the pathogenesis of pediatric [B-cell ALL] and the biological basis of the B-ALL health disparity in H/L children.”

References:

1. Raca G, Abdel-Azim H, Yue F, et al. Increased incidence of IKZF1 deletions and IGH-CRLF2 translocations in B-ALL of Hispanic/Latino children—a novel health disparity. Leukemia. Published online February 2, 2021. doi: 10.1038/s41375-021-01133-4

2. Harvey RC, Mullighan CG, Chen IM, et al. Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia. Blood. 2010;115(Jul):5312-5321. doi: 10.1182/blood-2009-09-245944