Autophagy in Hematological Malignancies: Molecular Aspects in Leukemia and Lymphoma

Hassan Boustani, MSc; Elahe Khodadi, MSc; Minoo Shahidi, PhD

Disclosures

Lab Med. 2021;52(1):16-23. 

In This Article

Autophagy in Lymphoid Malignancies

B- and T-lymphoblastic Leukemia/Lymphoma

Acute lymphoid leukemia (ALL) is the most common blood malignant neoplasm in children and accounts for 20% of adult leukemia cases.[36] This heterogeneous disorder involves different genomic changes, such as changes in the number and structure of chromosomes, and changes in the number of copies and mutations of DNA. This malignant neoplasm mainly occurs in B-cell precursors (B-ALL; 80%) and 20% in thymocytes (T-ALL). The results of a study[36] of 1 splice variant in Beclin-1 (BECN1) in the ALL 697 cell line with deletion in exon 11 have shown a decrease in autophagy induction in this malignant neoplasm.

We note that the ALL 697 cell line in the vicinity of Bafilomycin A1 decreased the graft in NOD/SCID mice. However, chromosomal translocation t (1;19) in pre-B acute lymphoblastic leukemia (pre-B ALL) in children induces autophagy in the face of rapamycin, leading to destruction of POLD1 DNA and RNA pol, and inhibits cell growth.[37] Also, using Torin-2 in pre-B ALL cells inhibits mTOR activity, enhances autophagy, and inhibits cell growth, which points to a tumor-suppressor role in autophagy.[38]

The role of autophagy in lymphoid malignant neoplasms is still controversial and may be observed in a specific subgroup. Further studies are needed to better understand the role of this recycling mechanism in leukemogenesis in the lymphoid lineage.

Chronic Lymphoid Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)

B-cell chronic lymphocytic leukemia (B-CLL)/SLL occurs predominantly in older adults and is characterized by inherent defects in cell death. This malignancy progresses slowly and shows clinical symptoms in afflicted patients. Study results[39] have shown that RNA inhibition of autophagy by targeting key autophagy genes in patients with CLL reduces cell survival.

Autophagy is also required for Toll-like receptor 9 (TLR9)–dependent secretion of immunoglobulin M (IgM) in a CLL-positive mouse model. High expression of phosphoinositide 3-kinase (PI3K), phosphoinositide-3-kinase regulatory subunit 4 (PIK3R4), and BECN1 is also associated with poor clinical outcome.[40]

Death-associated protein kinase 1 (DAPK1) is an autophagy-dependent gene 114; in rare cases of CLL, mutation in this gene increases HOXB7 binding to its promoter.[41] The loss of DAPK1 expression in CLL is due to a defect in the CCAAT-enhancer-binding proteins–activating transcription factor 6 (CEBP-ATF6) pathway function. Inhibition of DAPK1 reduces autophagy and increases the growth and proliferation of CLL cells.[42]

The dual role of autophagy in cancer has been proven in various studies. Signaling lymphocytic activation molecule family member 1 (SLAMF1) expression is associated with a favorable prognosis in patients with CLL and disappears in its invasive form.[43] Study results[43] have shown that SLAMF1 activates autophagy by stabilizing the BECN1-VPS34 complex; cells without SLAMF1 are less sensitive to autophagy-induced treatment.

Diffused Large Cell B Lymphoma (DLBCL)

DLBCL accounts for approximately 33% of B–non-Hodgkin lymphoma (B-NHL) and is the most common subgroup. DLBCL is an invasive lymphoma, de novo or the result of clinical progression of less-invasive B-NHL types (such as follicular lymphoma [FL] and CLL).

The 2016 World Health Organization (WHO) classification[44] introduced a new category of lymphomas, described as high-grade B-cell lymphoma with translocations related to MYC and B-cell lymphoma (BCL)–2 or BCL-6. BCL-2 directly inhibits autophagy by binding to BECN1; patients with decreased levels of BCL-2 show increased expression of BECN1, with favorable clinical outcomes.[45,46] Study results[47,48] have shown that in +/− BECN1 mice, the incidence of cancers such as lung, liver cancer, or B-cell lymphoma is higher. Other study results[49] have shown that inhibition of autophagic responses to DLBCL induced by BCL-6 may lead to lymphomagenesis. Also, a link between Cullin-4B (CUL4B) and autophagy and DLBCL progress has been observed.[50] CUL4B regulates autophagy through c-Jun N-terminal kinases (JNK signaling); inhibition of cell proliferation by deletion mutation in CUL4B may inhibit autophagy-mediated cell survival. This finding highlights the complexity of autophagy pathways in the DLBCL.

Mantle Cell Lymphoma (MCL)

MCL is an invasive disease in older adults that accounts for approximately 5% of B-NHL. It is associated with high expression of tissue transglutaminase (TG2) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB).[51] Decreased expression of TG2 causes proliferation of cells in this disease. Also, TG2 regulates autophagy, and inhibition of autophagy by the ATG5 gene-silencing results in TG2 loss of expression. In addition, ATG5-free cells reproduce less slowly than cells with autophagy.

Phospholipid scramblase 1 (PLSCR1) is a proapoptotic gene that, through 9-cis-retinoic and interferon-α, decreases its expression in MCL cells.[52,53] Also, PLSCR1 inhibits autophagy and reduces the survival of malignant cells in MCL.[54] In contrast, the hedgehog (hH) pathway in MCL cells increases the penetration of malignant cells into the BM. Inhibition of the hH pathway using LDE225 increased C-X-C chemokine receptor type 4 (CXCR-4) expression and, consequently, ROS increased autophagy activity and cell survival.[55]

Burkitt Lymphoma (BL)

BL is an invasive disease in immature B cells that is known by the rearrangement of the MYC gene, with early B cell markers testing positive for the disease and the involved cells having a high mitosis rate. BL is a rare disease that accounts for 1% to 2% of B-NHL cases in adults and 30% of pediatric lymphoma cases. The findings of a study on e-myc transgenic mice[56] have shown that dysfunction of lysosomes using chloroquine has prevented lymphomagenesis, suggesting the association of lymphomagenesis with autophagy in these patients.

Multiple Myeloma (MM)

MM is a plasma B-cell cancer that invades the BM, is associated with high genomic and phenotypic diversity, and is observed in elderly patients.[57] Intron 6 of ATG5 on chromosome 6q21 is a risk loci associated with a high probability of developing MM.[58,59] High expression of BECN1 or microtubule-associated protein 1A/1B-light chain 3 (LC3) is also associated with favorable clinical outcomes.[60] This finding suggests that autophagic dysfunction is crucial to the progression of MM disease.

However, findings from other studies indicate that activation of autophagy is essential for MM survival. A recent publication[61] reports that the role of myeloid-derived suppressor cells (MDSCs) in enhancing survival and proliferation of MM cells by activating the AMPK pathway has been demonstrated and that the prosurvival effect on AMPK may be due to autophagy induction. It has also been shown[62] in BM cells of patients with MM that overexpression of long noncoding RNA metastasis-associated lung adenocarcinoma transcript–1 (MALAT-1) and high mobility group box 1 (HMGB1) results in autophagy and survival.

CHE-1 protein, which is antiapoptotic, interacts with RNA polymerase II and regulates its expression. Expression of this protein is associated with MM progression and is essential for cell growth and survival. CHE-1 is phosphorylated by cellular stress and, by binding to the Redd1 and Deptor promoters, increases their expression and thereby decreases mammalian target of rapamycin complex (mTORC) activity. Expression of CHE-1 induces autophagy activity by induction of mTORC1 and mTORC2, indicating its association with autophagy in MM.[63] The results of several studies, such as Hoang et al,[64] have shown that inhibition of autophagy decreases cell survival in MM. However, other study results[65] point to the role of cell death and its association with autophagy in MM cells.

Anaplastic Large Cell Lymphoma (ALCL)

ALCL accounts for 1% to 3% of adult T-NHL lymphoma and 15% of pediatric lymphoma.[66] The role of autophagy in the development of ALCL has not been determined, to our knowledge. The results of a study[67] using derived cell lines have shown that inhibition of autophagy by small interfering RNA (siRNA) binding to ATG7 or chloroquine has no effect on cell viability.

FL

FL accounts for approximately 20% of B-NHL and is the second most common form of lymphoma worldwide.[68,69] Due to the role of autophagy in the regulation of B-cells, study results[70] have shown that patients with FL had a significant decrease in SQSMT1/p62 and LC3 levels, compared with reactive B-cells; this finding indicates increased autophagy activity in FL. The impairment of autophagy regulation in FL is not associated with overexpression of BCL-2. FL is associated with overexpression of LC3A and overexpression of hypoxia-inducible factor 1 (HIF-1), indicating its association with hypoxia, and has autophagic activity in FL.[71]

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