SOX6 blocks the proliferation of BCR-ABL1+ and JAK2V617F+ leukemic cells

Gloria Barbarani,Cristina Fugazza,Antonella E. Ronchi,Silvia M. L. Barabino

doi:10.1038/s41598-019-39926-4

Gloria Barbarani, Cristina Fugazza + Show 2 more

Open Access

https://doi.org/10.1038/s41598-019-39926-4

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Journal: Scientific Reports	Publication Date: Mar 4, 2019
Citations: 15	License type: open-access

Affiliation: University of Milano-Bicocca

Abstract

SOX6 is a HMG-box transcription factor expressed in a wide range of tissues. Recent data show that SOX6 expression is altered in different cancers, in the majority of cases being downregulated. To date, no data are available about SOX6 role in hematological malignancies. Here we demonstrate that SOX6 overexpressing BCR-ABL1+ B-ALL cells are unable to promote leukemia in a mouse model. Starting from this observation, we extended our study to a panel of human leukemic cells carrying genetic lesions distinctive of different types of leukemias and myeloproliferative disorders (the BCR-ABL1 translocation and the JAK2V617F amino acid substitution) to dissect the cellular events induced by SOX6. The inhibition of proliferation is the invariant outcome of SOX6 overexpression but it is achieved via two different cellular responses: terminal differentiation in erythroid-biased cells, irrespectively of their mutation, and apoptosis in megakaryocytic-primed and lymphoid cells. Within this context, cells carrying the highest copy number of the JAK2V617F allele better counteract the SOX6-imposed growth arrest. The interrogation of the GEPIA (Gene Expression Profiling Interactive Analysis) human dataset reveals that SOX6 is downregulated in a cohort of AML patients, uncovering a wide anti-proliferative role of SOX6 in a variety of mutant backgrounds.

Highlights

The SOX6 transcription factor, belonging to the Sry-related HMG-box family, is expressed in several tissues during development, where it plays a key role in the transition from proliferating progenitors to functionally mature cells[1]
The BCR-ABL1 fusion protein is the hallmark of Chronic Myeloid Leukemia (CML)[14,15], but it is a frequent cytogenetic abnormality in precursor B-lymphoblastic leukemia (B-Acute Lymphoblastic Leukemia, B-ALL) found in adults[16] and, more rarely, in pediatric patients[17]
The JAK2V617F mutation is typical of myeloproliferative disorders (MPDs) and Acute Myeloid Leukemia (AML)[18]

Summary

Introduction

The SOX6 transcription factor, belonging to the Sry-related HMG-box family, is expressed in several tissues during development, where it plays a key role in the transition from proliferating progenitors to functionally mature cells[1]. GFP+ ΔNGFR+ cells were absent in cultures expanded ex vivo from the bone marrows of mice injected with SOX6-transduced cells (Fig. 1d).

Results

Conclusion