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

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