CRLF2 and IKZF1 abnormalities in Mexican children with acute lymphoblastic leukemia and recurrent gene fusions: exploring surrogate markers of signaling pathways

Abstract

The gene fusions BCR‐ABL1, TCF3‐PBX1, and ETV6‐RUNX1 are recurrent in B‐cell acute lymphoblastic leukemia (B‐ALL) and are found with low frequency in coexistence with CRLF2 (cytokine receptor‐like factor 2) rearrangements and overexpression. There is limited information regarding the CRLF2 abnormalities and dominant‐negative IKZF1 isoforms associated with surrogate markers of Jak2, ABL, and Ras signaling pathways. To assess this, we evaluated 24 Mexican children with B‐ALL positive for recurrent gene fusions at diagnosis. We found CRLF2 rearrangements and/or overexpression, dominant‐negative IKZF1 isoforms, and surrogate phosphorylated markers of signaling pathways coexisting with recurrent gene fusions. All the BCR‐ABL1 patients expressed CRLF2 and were positive for pCrkl (ABL); most of them were also positive for pStat5 (Jak2/Stat5) and negative for pErk (Ras). TCF3‐PBX1 patients with CRLF2 abnormalities were positive for pStat5, most of them were also positive for pCrkl, and two patients were also positive for pErk. One patient with ETV6‐RUNX1 and intracellular CRLF2 protein expressed pCrkl. In some cases, the activated signaling pathways were reverted in vitro by specific inhibitors. We further analyzed a TCF3‐PBX1 patient at relapse, identifying a clone with the recurrent gene fusion, P2RY8‐CRLF2, rearrangement, and phosphorylation of the three surrogate markers that we studied. These results agree with the previous reports regarding resistance to treatment observed in patients with recurrent gene fusions and coexisting CRLF2 gene abnormalities. A marker phosphorylation signature was identified in BCR‐ABL1 and TCF3‐PBX1 patients. To obtain useful information for the assessment of treatment in B‐ALL patients with recurrent gene fusions, we suggest that they should be evaluated at diagnosis for CRLF2 gene abnormalities and dominant‐negative IKZF1 isoforms, in addition to the analyses of activation and inhibition of signaling pathways.

Characterization of Philadelphia-like Pre-B Acute Lymphoblastic Leukemia: Experiences in Mexican Pediatric Patients

“…In addition to this, we observed a high frequency of iAMP21 in our patients, frequently associated with P2RY8::CRLF2 deletion, as well as the presence of IKZF1 abnormalities. Collectively, our results appear consistent with the ones previously reported in the literature [ 20 , 35 , 36 ]; hence, the detection of these lesions must be considered in the routine screening of genetic abnormalities in pre-B ALL in Mexican patients. Finally, as all these abnormalities require high-risk therapy regimens, which include the use of specific inhibitors, a mandatory routine identification of this genetically heterogeneous entity will have a positive contribution to the overall survival of Mexican patients [ 1 , 11 ].…”

“…The primer sets and probes for the genes of this assay are presented in Supplementary Table S3 . The cut-off value for the expression of each transcript was based on the analysis of quartiles and was set as previously described [ 36 , 39 ].…”

Persistently high incidence rates of childhood acute leukemias from 2010 to 2017 in Mexico City: A population study from the MIGICCL

“…The frequency of B-cell (88.7%) in our study is higher than the reported previously in MC (73.2-85.1%) (3,15,24,132) but is similar to worldwide reported frequencies (80-92%) (111,112), except to that reported in Asian countries (92.7%) (132). These differences could be associated with the genetic profile of our population with B-cell, as reported in a study by , who report a high frequency (54.1%) of dominant-negative IKZF1 isoform transcripts in a pediatric population from a single medical institution (133). One of the reasons why there is a greater frequency of B-cell among Hispanics may be its relationship with IKZF1 and ARID5B, which have also been reported more frequently in Hispanics.…”