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RASD1 INHIBITS THE PROLIFERATION OF LEUKEMIA CELLS AND CORRELATES WITH LEUKEMIA RELAPSE IN ADULTS WITH PHILADELPHIA CHROMOSOME-NEGATIVE B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA

PF166

Lu, R.-Q.1, 2, 3; Wu, L.-X.1, 2, 3; Zhang, J.1, 2, 3; Qin, Y.-Z.1, 2, 3; Liu, Y.-R.1, 2, 3; Lai, Y.-Y.1, 2, 3; Jiang, H.1, 2, 3; Jiang, Q.1, 2, 3; Chang, Y.-J.1, 2, 3; Ruan, G.-R.1, 2, 3; Huang, X.-J.1, 2, 3

doi: 10.1097/01.HS9.0000558880.88701.64
Poster Session I: Acute lymphoblastic leukemia - Biology & translational research
Free

1Collaborative Innovation Center of Hematology, Peking University

2Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation

3Peking University Peoples Hospital, Peking University Institute of Hematology, Beijing, China

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Background:

The prognosis of adult B-cell acute lymphoblastic leukemia (B-ALL) remains poor due to drug resistance and relapse although the remission rate reaches 80%˜90%. Identifying molecular abnormalities associated with important cellular activities may help to improve the B-ALL risk stratification and provide potential therapeutic targets. We have previously found that the transcript level of Ras-related dexamethasone-induced 1(RASD1) is abnormally increased in adult B-ALL bone marrow mononuclear cells (BMMNCs) by bioinformatics and quantitative PCR, suggesting that it may be involved in the pathogenesis of B-ALL. RASD1 is a member of the Ras superfamily. Its abnormal expression has been reported in multiple solid tumors. However, its clinical relevance and biological role in hematopoietic malignancies, especially in B-ALL remain to be elucidated.

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Aims:

To determine the clinical significance of RASD1 transcript levels in adult B-ALL and to study its biological role and the potential mechanism in B-ALL.

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Methods:

Quantitative real-time polymerase chain reaction(RT-qPCR) was used to detect RASD1 transcript levels in BMMNCs from 90 newly diagnosed Philadelphia chromosome(Ph)-negative B-ALL and 40 healthy donors. The correlation between RASD1 transcript levels and relapse was analyzed. The biological function and potential mechanism were studied with RASD1-overexpressing and knockdown human B-ALL cell lines constructed by lentiviral infection. A xeno-transplant mouse model was used to study the effect of RASD1 overexpression on proliferation in vivo.

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Results:

The transcript levels of RASD1 in bone marrow mononuclear cells from 90 Philadelphia chromosome(Ph)-negative adult B-ALL (81.76%, 0.22%˜1824.52%) were significantly higher than those of 40 healthy controls (7.59%, 0.46%˜38.66%, P < 0.001). Patients with low RASD1 transcript levels had a significantly higher 5-year cumulative incidence of relapse (CIR, 52.0% [37.4%, 66.6%] vs. 36.2% [22.2%,50.2%]; P = 0.013) and a lower relapse-free survival (RFS, 47.5% [32.9%,62.1%] vs. 63.1% [49.0%,77.2%]; P = 0.012) than patients with high RASD1 transcription levels. Multivariate analysis showed that low RASD1 transcript level was an independent risk factors for CIR and RFS in patients with Ph-negative B-ALL (CIR: HR = 3.367[1.668,6.796], P = 0.001; RFS:HR = 2.938 [1.427,6.047], P = 0.003). Functional analysis showed that overexpression of RASD1 in BALL-1 and Nalm6 cells inhibited cell proliferation, cell cycle progression and survival after exposure to chemotherapeutics including daunorubicin, methotrexate and cytarabine. In contrast, RASD1 knockdown in Sup-B15 cells showed the opposite effects. The role of RASD1 in inhibiting cell growth was verified in a tumor-bearing mouse model. Western Blot showed that overexpression of RASD1 caused decreased levels of mTOR and p70S6K phosphorylation, increased expression of LC3BII/I and Beclin-1, suggesting that mTOR/p70S6K signaling pathway and autophagy may be involved in RASD1-mediated regulation of cell proliferation.

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Summary/Conclusion:

The transcript levels of RASD1 in BMMNCs from newly diagnosed Ph-negative adult B-ALL were significantly higher than those of healthy controls. A low RASD1 transcript level was independently correlated with a higher CIR and a lower RFS. Overexpression of RASD1 inhibited cell proliferation both in vitro and in vivo. mTOR/p70S6K signaling pathway and autophagy may be involved in RASD1-mediated regulation of proliferation in B-ALL cells.

Copyright © 2019 The Authors. Published by Wolters Kluwer Health Inc., on behalf of the European Hematology Association.