Philadelphia chromosome-negative B-cell acute lymphoblastic leukaemia with kinase fusions in Taiwan

Yin-Chen Hsu,Chih‐Hsiang Yu ,Sung‐Liang Yu ,Dong‐Tsamn Lin ,Kai‐Hsin Lin ,Shiann-Tarng Jou,Kathryn G Roberts,Yu‐Ling Ni ,Shu‐Huey Chen ,Shu‐Wha Lin ,Kang‐Hsi Wu ,Chia‐Hao Chang ,Meng‐Yao Lu ,Charles G Mullighan,Bing-Ching Ho,Yanming Chen ,Hong-Yeh Chang ,Ze‐Shiang Lin ,Wei-Tzu Chiu,Yung‐Li Yang

doi:10.1038/s41598-021-85213-6

Abstract

Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukaemia (ALL), a high-risk subtype characterised by genomic alterations that activate cytokine receptor and kinase signalling, is associated with inferior outcomes in most childhood ALL clinical trials. Half of the patients with Ph-like ALL have kinase rearrangements or fusions. We examined the frequency and spectrum of these fusions using a retrospective cohort of 212 newly diagnosed patients with childhood B-cell ALL. Samples without known chromosomal alterations were subject to multiplex reverse transcription polymerase chain reaction to identify known Ph-like kinase fusions. Immunoglobulin heavy chain locus (IGH) capture and kinase capture were applied to samples without known kinase fusions. We detected known kinase fusions in five of 212 patients, comprising EBF1-PDGFRB, ETV6-ABL1, ZC3HAV1-ABL2, EPOR-IGH, and CNTRL-ABL1. Two patients with P2RY8-CRLF2 were identified. Patients with non-Ph kinase fusions had inferior 5-year event-free survival and overall survival compared with patients with other common genetic alterations. The prevalence of non-Ph kinase fusions in our Taiwanese cohort was lower than that reported in Caucasian populations. Future clinical trials with tyrosine kinase inhibitors may be indicated in Taiwan because of the inferior outcomes for B-cell ALL with kinase fusions.

Highlights

Multiple genetic subtypes have prognostic implications and clinical significance in acute lymphoblastic leukaemia (ALL)
The remaining patients with Philadelphia chromosome-like (Ph-like) ALL have a variety of kinase alterations, including fusions involving ABL-class genes (ABL1, ABL2, CSF1R, PDGFRB, and PDGFRA) that are sensitive to ABL1 tyrosine kinase inhibitors (TKIs), rearrangements that create JAK2 fusion proteins or truncating rearrangements of the erythropoietin receptor (EPOR) that are sensitive to ruxolitinib in vitro[3,4,21,27,33]
The remaining 67 patients were analysed for additional kinase alterations, initially using reverse transcription (RT)-polymerase chain reaction (PCR) for known fusions and, if negative, by kinome capture followed by next-generation sequencing (NGS)

Summary

Introduction

Multiple genetic subtypes have prognostic implications and clinical significance in acute lymphoblastic leukaemia (ALL) These ALL-associated genetic alterations include aneuploidy, copy number variations, sequence mutations, and chromosomal translocations that result in aberrant expressions of oncogenes or the construction of chimeric fusion genes[1]. Reshmi et al used low-density array (LDA) to screen Ph-like ALL, followed by multiplex reverse transcription (RT) polymerase chain reaction (PCR) to identify known Ph-like kinase fusions. They used kinome kits with next-generation sequencing (NGS) or RNA-seq on Ph-like ALL samples without known kinase fusions and demonstrated the feasibility of their strategy in clinical p ractice[21]. We modified the strategy proposed by Reshmi et al to identify the kinase fusions in childhood B-ALL in this retrospective study[21]

Methods

Results

Conclusion