Abstract 4623

Introduction:

Autophagy is a catabolic pathway by which cytoplasmic materials are degraded into the lysosome and it is also a quality control system for proteins and organelles. Autophagy plays an important role in cell adaptation to starvation, hypoxia, cell survival and cancer. Its core molecular machinery is tightly linked to metabolic pathways, such as LKB1/AMPK and mTORC1. Autophagy has been shown to play several important roles in cancer. Indeed, multiple autophagy genes have been characterized as tumor suppressor genes. In hematopoietic system, autophagy is required during myeloid and lymphoid differentiation, terminal erythroid mitochondrial clearance, production of proplatelets and also differentiation of monocytes into macrophages. Interestingly, autophagy seems disturbed in most bone marrow malignancies. Evidence in mice suggests that autophagy suppression (ATG7 or ATG5 knockdown models) in hematopoietic stem cells may be implicated in Acute Myeloid Leukemia (AML) pathogenesis. In Multiple Myeloma (MM), in vitro studies using cell lines showed autophagy activation and lysosome inhibitors (such as chloroquine) are currently been used in various combination treatments in clinical trials.

Aim:

The aim was to characterize the expression of autophagy machinery key genes (BECN1, MAP1LC3A, SQSTM1), as well as hypoxia master regulator (HIF1A) in total bone marrow cells from bone marrow malignancies: myelodysplasia (MDS), MM and AML patients, excluding acute promyelocytic leukemia.

Methods:

BECN1, MAP1LC3A, SQSTM1 and HIF1A levels were verified, by q-PCR, in diagnostic (or without any treatment) BM aspirates from 22 normal donors, 30 MDS (17 low-risk and 13 high-risk, according 2008 WHO classification), 43 AML and 11 MM patients.

Results:

BECN1 gene expression was increased in MM, compared with control group. All other groups did not differ from the control group. Comparing diseases amongst each other, AML had a lower BECN1 expression, compared with low-risk MDS and with MM (Figure 1A).

Figure 1
Figure 1. – Relative gene expression of BECN1 (A), MAP1LC3A (B), SQSTM1 (C) and HIF1A (D) in Bone Marrow Malignancies (AML, low-risk MDS, high-risk MDS and MM, respectively)
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– Relative gene expression of BECN1 (A), MAP1LC3A (B), SQSTM1 (C) and HIF1A (D) in Bone Marrow Malignancies (AML, low-risk MDS, high-risk MDS and MM, respectively)

Figure 1
Figure 1. – Relative gene expression of BECN1 (A), MAP1LC3A (B), SQSTM1 (C) and HIF1A (D) in Bone Marrow Malignancies (AML, low-risk MDS, high-risk MDS and MM, respectively)
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– Relative gene expression of BECN1 (A), MAP1LC3A (B), SQSTM1 (C) and HIF1A (D) in Bone Marrow Malignancies (AML, low-risk MDS, high-risk MDS and MM, respectively)

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Disclosures:

No relevant conflicts of interest to declare.

Topics:
autophagy, bone marrow, cancer, hypoxia inducible factor 1, alpha subunit, hypoxia, acute promyelocytic leukemia, chloroquine, leukemia, myelocytic, acute, multiple myeloma, myelodysplastic syndrome

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2012 by The American Society of Hematology
2012
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