Multi-Lineage BCR-ABL Expression in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Is Associated With Improved Prognosis but No Specific Molecular Features

Satoshi Nishiwaki; Jeong Hui Kim; Masafumi Ito; Matsuyoshi Maeda; Yusuke Okuno; Daisuke Koyama; Yukiyasu Ozawa; Masaharu Gunji; Masahide Osaki; Kunio Kitamura; Yoko Ushijima; Yuichi Ishikawa; Koichi Miyamura; Isamu Sugiura; Hitoshi Kiyoi

doi:10.3389/fonc.2020.586567

Multi-Lineage BCR-ABL Expression in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Is Associated With Improved Prognosis but No Specific Molecular Features

Front Oncol. 2020 Oct 23:10:586567. doi: 10.3389/fonc.2020.586567. eCollection 2020.

Authors

Affiliations

¹ Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Japan.
² Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
³ Department of Pathology, Japanese Red Cross Nagoya Daiichi Hospital, Nagoya, Japan.
⁴ Division of Pathology, Toyohashi Municipal Hospital, Toyohashi, Japan.
⁵ Medical Genomics Center, Nagoya University Hospital, Nagoya, Japan.
⁶ Division of Hematology and Oncology, Toyohashi Municipal Hospital, Toyohashi, Japan.
⁷ Department of Hematology, Japanese Red Cross Nagoya Daiichi Hospital, Nagoya, Japan.
⁸ Division of Hematology, Ichinomiya Municipal Hospital, Ichinomiya, Japan.

Abstract

Background: Recently, various blood cell lineages expressing the BCR-ABL fusion gene in Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) have been reported. However, the biological and clinical significance of these BCR-ABL lineages has not been established; therefore, we aimed to clarify the impacts of these different BCR-ABL-expressing lineages.

Patients: Multi-lineage BCR-ABL expression (multi-Ph) was defined as BCR-ABL expression outside of the B-lineage compartment, as determined by fluorescence in situ hybridization (FISH) in peripheral blood neutrophils and bone marrow clots, and flow cytometry-sorted polymerase chain reaction (PCR). We analyzed IKZF1 deletion patterns by PCR, examined gene expression profiles using RNA sequencing, and compared treatment outcomes across different BCR-ABL-expressing lineages.

Results: Among the 21 multi-Ph patients in our 59-patient cohort (36%), BCR-ABL expression was detected at the multipotential progenitor level. However, no IKZF1 deletion patterns or gene expression profiles were identified that were specific for multi-Ph. However, multi-Ph patients were found to have better survival rates than patients with uni-lineage BCR-ABL expression [event-free survival (EFS): 74 vs. 33%, P = 0.01; overall survival (OS): 79 vs. 44% at 4 years, P = 0.01]. In multivariate analyses, multi-Ph was identified as a good prognostic factor for both EFS and OS.

Conclusion: We confirmed that more than one-third of Ph+ALL patients could be classified as mutli-Ph. Although no specific molecular characteristics were identified for multi-Ph, this phenotype was associated with better treatment outcomes.

Keywords: BCR-ABL-expressing lineage; Philadelphia chromosome-positive acute lymphoblastic leukemia; multi-lineage; multipotent progenitor; uni-lineage.