Extracellular matrix protein 1 (ECM1) is a potential biomarker in B cell acute lymphoblastic leukemia

Abstract

B cell acute lymphoblastic leukemia (ALL) is characterized by the highly heterogeneity of pathogenic genetic background, and there are still approximately 30-40% of patients without clear molecular markers. To identify the dysregulated genes in B cell ALL, we screened 30 newly diagnosed B cell ALL patients and 10 donors by gene expression profiling chip. We found that ECM1 transcription level was abnormally elevated in newly diagnosed B cell ALL and further verified in another 267 cases compared with donors (median, 124.57% vs. 7.14%, P < 0.001). ROC analysis showed that the area under the curve of ECM1 transcription level at diagnosis was 0.89 (P < 0.001). Patients with BCR::ABL1 and IKZF1 deletion show highest transcription level (210.78%) compared with KMT2A rearrangement (39.48%) and TCF3::PBX1 rearrangement ones (30.02%) (all P < 0.05). Also, the transcription level of ECM1 was highly correlated with the clinical course, as 20 consecutive follow-up cases indicated. The 5-year OS of patients (non-KMT2A and non-TCF3::PBX1 rearrangement) with high ECM1 transcription level was significantly worse than the lower ones (18.7% vs. 72.9%, P < 0.001) and high ECM1 transcription level was an independent risk factor for OS (HR = 5.77 [1.75-19.06], P = 0.004). After considering transplantation, high ECM1 transcription level was not an independent risk factor, although OS was still poor (low vs. high, 71.1% vs. 56.8%, P = 0.038). Our findings suggested that ECM1 may be a potential molecular marker for diagnosis, minimal residual disease (MRD) monitoring, and prognosis prediction of B cell ALL.Trial registration Trial Registration Registered in the Beijing Municipal Health Bureau Registration N 2007-1007 and in the Chinese Clinical Trial Registry [ChiCTR-OCH-10000940 and ChiCTR-OPC-14005546]; http://www.chictr.org.cn .

Keywords: ECM1; B cell acute lymphoblastic leukemia; Diagnosis; MRD; Prognosis.

Fig. 1

Up-regulated transcription level of ECM1 in newly diagnosed B cell ALL. A Transcription level of ECM1 in B cell ALL (D newly diagnosed, CR complete remission, R relapse), normal donors, and AML (D newly diagnosed, CR complete remission). The original transcription level (ECM1/ABL1) was multiplied by 1000 times and then logarithmically conversed. B The ROC curve of ECM1 transcription levels for B cell ALL diagnosis

Fig. 2

Transcription levels of ECM1 in different B cell ALL subgroups. A Transcription levels of ECM1 in different genetic backgrounds. B Transcription levels of ECM1 in different immunophenotypes. The original transcription level (ECM1/ABL1) was multiplied by 1000 times and then logarithmically conversed. C–F The ROC curve of ECM1 transcription level in the double-negative, IKZF1-positive, BCR:ABL1-positive, and double-positive groups, respectively. **: P < 0.01, ***: P < 0.001

Fig. 3

MRD monitored by different indicators. A The correlation between ECM1 transcription level and clinical course in consecutive 20 patients. The original transcription level (ECM1/ABL1) was multiplied by 1000 times and then logarithmically conversed. B–F Transcription level of ECM1 and other clinical MRD monitoring indicators in 5 long-term follow-up patients. Samples at diagnosis, relapse, molecular relapse, and extramedullary relapse were marked, while the remaining unlabeled points indicated complete remission. The actual MRD levels of each indicator were shown in patients 1–4. Due to the significant difference in transcription levels between ECM1 and WT1 in patient 5, ECM1 was multiplied by 1000 times and then logarithmically conversed, while WT1 was multiplied by 10,000 times and then logarithmically conversed, corresponding to the left axis. The blue dashed line represented to the WT1 threshold (0.60%). Bone marrow morphology and flow cytometry were showed as the actual MRD levels, corresponding to the right axis. D diagnosis, CR complete remission, R relapse, T transplantation, CNS central nerve system, BM bone marrow morphology, FC flow cytometry

Fig. 4

Prognostic analysis of ECM1 in B cell ALL patients. A OS analysis with transplantation as censored event. B OS analysis with transplantation not as censored event

Fig. 5

KEGG analysis of B cell ALL patients with high ECM1 transcription level. A Leukocyte transendothelial migration, B Adherens junction, C Regulation of actin cytoskeleton