Abstract

Introduction

“Ph-like acute lymphoblastic leukemia (ALL)” or “BCR-ABL1-like ALL” is a recently identified subtype of high-risk B-cell precursor (BCP)-ALL with poor outcome and high frequency of IKZF1 deletion. They exhibit a gene expression profile similar to BCR-ABL1-positive (Ph1-)ALL but do not have BCR-ABL1 and other common chimeric genes. Recent study from others has identified rearrangements involving tyrosine kinase genes, such as ABL1, PDGFRB, JAK2, and CRLF2, by employing transcriptome sequencing using next generation sequencer. In the present study, we intended to explore the biologic characteristics and clinical outcomes of Ph-like ALL cases in Japanese patients.

Method

We investigated gene expression of 235 BCP-ALL cases enrolled on Tokyo Children Cancer Study Group (TCCSG) L0416 and L0616 trials by microarray GeneChip Human Genome U133 Plus 2.0 and analyzed using both clustering analysis and Gene Set Enrichment Analysis (GSEA), a computational method that ascertains whether a given gene set is significantly enriched in a list of genes ranked by their correlation with a phenotype of interest. Four-year event-free survival (EFS) rate of the entire cases was 83.2%.

Results

Real-time PCR analysis revealed that 155 cases did not have common chimeric genes (“chimera-”), including BCR-ABL1, ETV6-RUNX1, E2A-PBX1, MLL-AF4, MLL-AF9, and MLL-ENL. Among “chimera-” cases, 11 (4.7% of the entire BCP-ALL cases) patients were identified as ALL with gene expression profile similar to that of Ph1-ALL by clustering analysis. Their 4-year EFS rate and the frequency of IKZF1 deletion were 66.7% and 80.0%, respectively.

On the other hand, GSEA detected 26 ALL cases with Ph-like signature (11.1%), including 9 cases those identified to have Ph-like phenotype by clustering analysis, and they exhibited 4-year EFS rate of 58.3% and IKZF1 deletion frequency of 38.1%. Interestingly, GSEA also revealed that 7 cases simultaneously possess ETV6-RUNX1-like signature. When we excluded 7 cases having ETV6-RUNX1-like signature and 5 cases with higher NOM p-value than 0.05, 14 cases were remained and they represented a highly unfavorable outcome (event-free survival 38.1%), while the frequency of IKZF1 deletion was 41.7%.

We performed transcriptome sequencing of ALL cases with Ph-like phenotype using next generation sequencer and identified rare and novel chimeric fusions involving tyrosine kinases, such as ABL1, as well as CRLF2-related chimeric fusions.

Conclusions

We identified the presence of ALL subset having Ph-like phenotype in Japanese patients. They represent unfavorable outcome. However, the diagnosis of “Ph-like ALL” varies according to the method to identify Ph-like phenotype. Therefore, the definition of “Ph-like ALL” needs more consideration.

Table

Characteristics of BCP-ALL* 1 with Ph-like phenotype

 BCP-ALL-Total Ph-like-clustering Ph-like-GSEA*2 Ph-like-GSEA-restricted*3 
Case No. 235 11 (4.7%) 26 (11.1%) 14 (6.0%) 
Age (mean) 5.7 10.3 6.6 8.3 
Initial WBC count/µl (mean) 35,389 157,506 66,257 86,293 
4-year event free survival 83.2% 66.7% 58.3% 38.5% 
IKZF1-deletion 11.9% 80.0% 38.1% 41.7% 
 BCP-ALL-Total Ph-like-clustering Ph-like-GSEA*2 Ph-like-GSEA-restricted*3 
Case No. 235 11 (4.7%) 26 (11.1%) 14 (6.0%) 
Age (mean) 5.7 10.3 6.6 8.3 
Initial WBC count/µl (mean) 35,389 157,506 66,257 86,293 
4-year event free survival 83.2% 66.7% 58.3% 38.5% 
IKZF1-deletion 11.9% 80.0% 38.1% 41.7% 

*1BCP-ALL; B-cell precursor-acute lymphoblastic leukemia

*2GSEA; Gene Set Enrichment Anlysis

* 3GSEA-restricted; excluding ETV6-RUNX1-like and NOM p-value>0.05 cases

Disclosures:

No relevant conflicts of interest to declare.

Author notes

*

Asterisk with author names denotes non-ASH members.

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