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 Myeloid Malignant Neoplasms

Acute Myeloid Leukemia (AML)

AML, the most common type of leukemia in older adults (80%), is characterized by arrest of myeloid differentiation and inappropriate proliferation and survival in leukemic blast cells associated with high clinical heterogeneity among individuals. Evidences[12,13] suggest that primary blasts in AML have lower autophagy gene levels, compared with nonleukemic cells or AML differentiation cells. Similarly, increased expression of autophagy receptor SQSMT1/p62 has been observed[14] during neutrophil differentiation in acute promyelocytic leukemia (APL) cells.

It has also been reported[14] that microRNA (miR)–17, -20, -93, and -106, which target SQSMT1/p62, are higher in mouse and human blast cells than in neutrophils. Increased expression of SQSMT1/p62 is thought[15,16] to prevent ubiquitinated protein accumulation. During the final differentiation of APL cells, it acts as a prosurvival cellular mechanism. Recent evidence[17] also suggests that SQSMT1/p62 is essential for cell growth and maintaining mitochondrial integrity. In fact, defects in SQSMT1/p62 impair the progression of myeloid leukemia and mitophagy in this type of malignant neoplasm.

Numerous articles in the literature support the idea that the role of autophagy in the progression of leukemia varies depending on the type of oncogene that can affect disease progression. The RET proto-oncogene is a tyrosine kinase that has recently been identified[18] as a key kinase in AML. Activated RET pathways lead to decreased autophagy and stability of leukemia-causing factors, such as mutant FMS-like tyrosine kinase 3 (FLT3). Also, RET inhibition leads to decreased FLT3 through autophagy. However, proteasome inhibitors increase FLT3 internal tandem duplication (FLT3/ITD) degeneration through autophagy.[19]

In contrast, inhibition of the FLT3-ITD mutation in AML cells, by impairing autophagy-dependent proliferation in vitro and in vivo, enhances a high level of basal autophagy. This FLT3-ITD–dependent autophagy depends on the extent of ATF4 transcription.[20] In AML cells mutated with nucleophosmin 1 (NPM), promyelocytic leukemia (PML) protein remains stable in the cytoplasm. PML insertion in the cytoplasm leads to serine/threonine-protein kinases (Akt) phosphorylation, which subsequently results in prosurvival autophagy.[21]

In studies of MLL-ENL mouse models, inhibition of autophagy by ATG7 deletion leads to decreased leukemia-initiating cells (LICs) and stronger survival in leukemic mice. These conditions led to an increase in ROS production, along with an increase in mitochondrial activity and cell death. Accordingly, blasts of this mouse model were reduced in peripheral blood due to increased apoptosis.[22]

Study results have shown that in the mixed lineage leukemia–eleven nineteen lysine-rich leukemia (MLL-ENL) mouse model, inhibition of autophagy by removing autophagy-related 7 (ATG7) or autophagy-related 5 (ATG5) results in more aggressive leukemia in vivo. In addition, these results showed that MLL-ENL cells with decreased autophagy activity lead to abnormal activity in mitochondria—specifically, proliferation and transformation.

In the acute myelogenous leukemia–1 eight-twenty-one oncoprotein (AML1-ETO) AML mouse model, autophagy inhibited LIC proliferation.[23] Mixed-lineage leukemia (MLL-Af9, or MA9) AML cells exhibit more autophagic activity than normal bone marrow (BM). However, degradation of Rb1cc1 or ATG5 does not affect the growth or survival of MA9-AML cells, in vitro and in vivo.[24] Study results[25] have shown that autophagy activity is required for malignancy but not required for maintenance of malignancy in MLL-Af9 AML cells.

The H2.0-like homeobox transcription factor (HLX), which shows increased expression in AML, is another factor involved in the regulation of hematopoietic differentiation. Increased expression of HLX has been reported to induce 5' AMP-activated protein kinase (AMPK) activation and survival of AML cells through autophagy.[26] Overall, AML is a heterogeneous disease, and so autophagy acts as a tumor promoter and suppressor, depending on the AML subtype.

Chronic Myeloid Leukemia (CML)

CML accounts for 15% of all types of leukemia in adults, with displacement of t(22;9)(q34;q11) and expression of the breakpoint cluster region protein–Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL) fusion protein, which has excessive tyrosine kinase activity. Study results[26] have shown that BCR-ABL1 induces MAPK15-dependent autophagy and causes cell transformation. However, other study results[27] have shown that BCR-ABL inhibits ATF5-dependent autophagy only in transformed cells. Lys05, the second generation of autophagy inhibitors, results in quiescence of CML stem cells and reduces the maturation of these cells. Also, Lys05 or PIK-III (PtIns3P class III inhibitor), when selectively combined with a tyrosine kinase inhibitor, reduced the number of primary CML LSCs. This finding suggests that this combination drug is associated with the destruction of stem cells in patients with CML.[27]

By using a certain type of cell culture and keeping the cells primarily at low oxygen concentration and subsequently exposed to oxygen, KML5 cells need autophagy only for commitment and not for proliferation.[28] Also, BIM1 expression as a transcription factor promotes CML progression to acute stages.[29] In fact, BIM1 inhibition increases Cyclin-G2 (CCNG2) expression and decreases tumor suppressor response in autophagy.

Myelodysplastic Syndrome (MDS)

MDS comprises a heterogeneous class of blood disorders.[30,31] It is divided into 4 main subgroups: MDS with single-lineage dysplasia, MDS with ring sideroblasts (MDS-RS), MDS with excess blasts, and MDS with isolated del(5q).

Numerous studies are underway to help researchers understand the effect of autophagy on the development and development of MDS. Increased expression of autophagy-related protein 2 homolog B (ATG2B) and GSK3B-interacting protein (GSKIP) caused changes in germline copy number in several myeloid malignant neoplasms.[32] However, study results[33] have shown that patients with MDS who harbor U2AF35 (S35F) mutation show an increase in pre-mRNA levels in ATG7 and have a distal cleft at the polyadenylation site, which reduce ATG7 expression and autophagy activity in cells. Nuclear red blood cells in patients with high-risk MDS have lower LC3B levels and greater mitochondrial deficiency; also, LC3B levels are correlated with hemoglobin levels in these patients.[34] In addition, ATG3 expression is lower in patients with MDS than in healthy control individuals, and overexpression of ATG3 in the SKM-1 MDS cell line increases caspase-dependent autophagy activity and cell death.[35]

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