Table 1 Role of MARCKS in hematological malignancies

Acute Myeloid Leukemia (AML)

Disease signature Disease progression

MARCKS is associated with receptor tyrosine kinase TrkA and KIT expression and is a marker of poor outcome in AML.

[116]

Chronic Myelogenous Leukemia (CML)

Disease development Disease signature

Evidence of alternative splicing in MARCKS was identified in leukemic stem cells in CML.

[117]

Chronic Myelogenous Leukemia (CML)

Disease development

MARCKS plays an important role in the differentiation process of human megakaryoblastic leukaemia cell line MEG-01 through its interaction with PKC.

[118]

Chronic Myelogenous Leukemia (CML)

Drug Target

Treatment of HUVECs with exosomes derived from CML cells treated with curcumin alone or enriched with miR-21 reduced MARCKS expression significantly.

[119]

Myeloid malignancies

Disease development Disease progression

NADPH oxidase signaling may be mediated through MARCKS phosphorylation of ED in myeloid malignancies.

[120]

Acute Lymphoblastic Leukemia (ALL)

Drug resistance Disease progression

(1) MARCKS is associated with poor prognosis in therapy-refractory leukemia patients, specifically treated with bortezomib.

(2) MARCKS is responsible for formation and exocytosis-mediated extrusion of ubiquitin-containing vesicles in bortezomib-resistant leukemic cells, reducing cellular proteasomal load, promoting cell-survival.

[15]

Chronic Lymphocytic Leukemia (CLL)

Disease occurrence

Incubation of B-CLL cells with phorbol esters resulted in the phosphorylation of PKC substrates MARCKS, MRP and a novel protein of apparent 60 kDa molecular weight.

[121]

Chronic Lymphocytic Leukemia (CLL)

Disease occurrence

Incubation of B-CLL cells with phorbol esters resulted in the phosphorylation of PKC substrates MARCKS, MRP and a novel protein of apparent 60 kDa molecular weight, subsequently characterized as lymphocyte-specific protein 1.

[122]

Mantle Cell Lymphoma (MCL) & Chronic Lymphocytic Leukemia (CLL)

Disease signature

(1) MARCKS is differentially expressed, localized and phosphorylated between MCL and CLL.

(2) Oncogenic miR-155 inhibits MARCKS expression in CLL.

(3) MARCKS has an important role in the MCL pathogenesis and can function as an MCL biomarker.

[19]

Mantle Cell Lymphoma

Disease signature

MARCKS is upregulated in the Blastoid Variant of Mantle Cell Lymphoma.

[123]

Mantle Cell Lymphoma

Disease signature

MARCKS is less expressed in Mantle Cell Lymphoma with low levels of the long cyclin D1 transcript as compared to other MCL with a higher expression of cyclin D1 variant.

[124]

Burkitt’s Lymphoma (BL)

Disease occurrence

MARCKS is one of the previously unknown genes found to be upregulated in Epstein-Barr virus infected B-lymphocytes.

[125]

B-cell lymphoma

Disease occurrence

Type-1 Epstein-Barr virus antigen 2 causes a significant induction of MARCKS in lymphoblastoid cell lines as compared to type-2 Epstein-Barr virus antigen 2.

[126]

Lymphoplasmacytic Lymphoma (Waldenström’s macroglobulinemia)

Disease signature

LEF1, MARCKS, ATXN1 and FMOD form a gene signature that can discriminate clonal B-lymphocytes from Waldenström’s macroglobulinemia and chronic lymphocytic leukemia

[127]

Lymphoplasmacytic Lymphoma (Waldenström’s macroglobulinemia)

Therapeutic target

Protein kinase C inhibitor Enzastaurin inhibits phosphorylation of MARCKS and other signaling molecules downstream of PKC, and subsequently induces anti-tumor activity in vitro and in vivo in Waldenström’s macroglobulinemia.

[16]

Diffuse large B cell lymphoma (DLBCL)

Disease progression Drug resistance

6q21 (near MARCKS and HDAC2 genes) was identified as one of the top loci marked with rs7765004 genetic variant associated with event-free survival and overall survival in patients with DLBCL.

[128]

Diffuse large B cell lymphoma (DLBCL)

Disease progression Drug resistance

Immunohistochemical staining shows a higher expression of MARCKS-like protein in DLBCL patients who remain progression-free for more than 5 years following initial diagnosis.

[129]

B-Cell tumor

Disease occurrence

(1) Unphosphorylated MARCKS suppressed proliferation and survival of B-cell tumor cells and splenic B cells in vitro and in vivo.

(2) MARCKS regulates strength of B-cell signaling by modulating cytoskeleton and plasma membrane interactions.

[130]

T-cell Lymphoma

Radiation resistance Disease progression

Frequent mutations were observed in MARCKS in spontaneous and infrared-radiation induced lymphomas in mice models with biallelic germline mutations in DNA mismatch repair gene MLH1.

[17]

Multiple Myeloma

Drug resistance

Disease progression

PKC-inhibitor enzastaurin inhibits phorbol ester-induced phosphorylation of MARCKS and other downstream signalling molecules.

[131]

Multiple Myeloma

Drug resistance

Disease progression Therapeutic target

(1) MARCKS is overexpressed in drug-resistant myeloma.

(2) Knockdown of MARCKS or inhibition of phosphorylation enhanced therapeutic sensitivity.

[14]

Multiple Myeloma

Drug resistance

Disease progression

(1) Jagged1 induced activation of Notch-PKC pathway in myeloma cells causes MARCKS to play vital roles in the development of drug-resistant myeloma cells.

(2) The PKC-MARCKS pathway is a vital druggable target in refractory multiple myeloma.

[18]

Multiple Myeloma

Drug resistance

Disease progression

(1) miR-34a regulates MARCKS expression.

(2) Combining traditional chemotherapy with MARCKS antagonists increases effectiveness against drug resistant MM cells

[132]