The Role Played by Wnt/β-Catenin Signaling Pathway in Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is an aggressive hematologic neoplastic disorder that arises from the clonal expansion of transformed T-cell or B-cell precursors. Thanks to progress in chemotherapy protocols, ALL outcome has significantly improved. However, drug-resistance remains an unresolved issue in the treatment of ALL and toxic effects limit dose escalation of current chemotherapeutics. Therefore, the identification of novel targeted therapies to support conventional chemotherapy is required. The Wnt/β-catenin pathway is a conserved signaling axis involved in several physiological processes such as development, differentiation, and adult tissue homeostasis. As a result, deregulation of this cascade is closely related to initiation and progression of various types of cancers, including hematological malignancies. In particular, deregulation of this signaling network is involved in the transformation of healthy HSCs in leukemic stem cells (LSCs), as well as cancer cell multi-drug-resistance. This review highlights the recent findings on the role of Wnt/β-catenin in hematopoietic malignancies and provides information on the current status of Wnt/β-catenin inhibitors with respect to their therapeutic potential in the treatment of ALL.

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Novel in vivo model of inducible multi-drug resistance in acute lymphoblastic leukemia with chromosomal translocation t(4;11)

Cancer Letters ◽

10.1016/j.canlet.2010.03.017 ◽

2010 ◽

Vol 296 (1) ◽

pp. 49-54 ◽

Cited By ~ 4

Author(s):

Susan J. Zunino ◽

David H. Storms ◽

Jonathan M. Ducore

Keyword(s):

Drug Resistance ◽

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Chromosomal Translocation ◽

Multi Drug Resistance ◽

In Vivo Model

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Death induction by CD99 ligation in TEL/AML1-positive acute lymphoblastic leukemia and normal B cell precursors

Journal of Leukocyte Biology ◽

10.1189/jlb.0210097 ◽

2010 ◽

Vol 88 (2) ◽

pp. 405-412 ◽

Cited By ~ 21

Author(s):

Z. Husak ◽

D. Printz ◽

A. Schumich ◽

U. Potschger ◽

M. N. Dworzak

Keyword(s):

Acute Lymphoblastic Leukemia ◽

B Cell ◽

Lymphoblastic Leukemia ◽

B Cell Precursors

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Autocrine IL-6/STAT3 signaling aids development of acquired drug resistance in Group 3 medulloblastoma

Cell Death and Disease ◽

10.1038/s41419-020-03241-y ◽

2020 ◽

Vol 11 (12) ◽

Author(s):

Lakshana Sreenivasan ◽

Hui Wang ◽

Shyong Quin Yap ◽

Pascal Leclair ◽

Anthony Tam ◽

...

Keyword(s):

Drug Resistance ◽

Multi Drug Resistance ◽

Acquired Drug Resistance ◽

Stat3 Signaling ◽

Therapeutic Benefits ◽

Signaling Axis ◽

Neuronal Precursors ◽

Cranial Fossa ◽

Group 3

AbstractMedulloblastoma (MB) is a high-grade pediatric brain malignancy that originates from neuronal precursors located in the posterior cranial fossa. In this study, we evaluated the role of STAT3 and IL-6 in a tumor microenvironment mediated drug resistance in human MBs. We established that the Group 3 MB cell line, Med8A, is chemosensitive (hence Med8A-S), and this is correlated with a basal low phosphorylated state of STAT3, while treatment with IL-6 induced robust increases in pY705-STAT3. Via incremental selection with vincristine, we derived the stably chemoresistant variant, Med8A-R, that exhibited multi-drug resistance, enhanced IL-6 induced pY705-STAT3 levels, and increased IL6R expression. Consequently, abrogation of STAT3 or IL6R expression in Med8A-R led to restored chemosensitivity to vincristine, highlighting a prominent role for canonical IL-6/STAT3 signaling in acquired drug resistance. Furthermore, Med8A-S subjected to conditioning exposure with IL-6, termed Med8A-IL6+ cells, exhibited enhanced vincristine resistance, increased expression of pY705-STAT3 and IL6R, and increased secretion of IL-6. When cocultured with Med8A-IL6+ cells, Med8A-S cells exhibited increased pY705-STAT3 and increased IL-6 secretion, suggesting a cytokine feedback loop responsible for amplifying STAT3 activity. Similar IL-6 induced phenomena were also observed in the Group 3 MB cell lines, D283 and D341, including increased pY705-STAT3, drug resistance, IL-6 secretion and IL6R expression. Our study unveiled autocrine IL-6 as a promoter of STAT3 signaling in development of drug resistance, and suggests therapeutic benefits for targeting the IL-6/STAT3 signaling axis in Group 3 MBs.

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Overcoming Microenvironment-Mediated Chemoprotection through Stromal Galectin-3 Inhibition in Acute Lymphoblastic Leukemia

International Journal of Molecular Sciences ◽

10.3390/ijms222212167 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12167

Author(s):

Somayeh S. Tarighat ◽

Fei Fei ◽

Eun Ji Joo ◽

Hisham Abdel-Azim ◽

Lu Yang ◽

...

Keyword(s):

Drug Resistance ◽

Acute Lymphoblastic Leukemia ◽

Stromal Cells ◽

Lymphoblastic Leukemia ◽

High Specificity ◽

Leukemia Cells ◽

Cell Precursor ◽

Cell Responses ◽

Galectin 3 ◽

Dose Dependent

Environmentally-mediated drug resistance in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) significantly contributes to relapse. Stromal cells in the bone marrow environment protect leukemia cells by secretion of chemokines as cues for BCP-ALL migration towards, and adhesion to, stroma. Stromal cells and BCP-ALL cells communicate through stromal galectin-3. Here, we investigated the significance of stromal galectin-3 to BCP-ALL cells. We used CRISPR/Cas9 genome editing to ablate galectin-3 in stromal cells and found that galectin-3 is dispensable for steady-state BCP-ALL proliferation and viability. However, efficient leukemia migration and adhesion to stromal cells are significantly dependent on stromal galectin-3. Importantly, the loss of stromal galectin-3 production sensitized BCP-ALL cells to conventional chemotherapy. We therefore tested novel carbohydrate-based small molecule compounds (Cpd14 and Cpd17) with high specificity for galectin-3. Consistent with results obtained using galectin-3-knockout stromal cells, treatment of stromal-BCP-ALL co-cultures inhibited BCP-ALL migration and adhesion. Moreover, these compounds induced anti-leukemic responses in BCP-ALL cells, including a dose-dependent reduction of viability and proliferation, the induction of apoptosis and, importantly, the inhibition of drug resistance. Collectively, these findings indicate galectin-3 regulates BCP-ALL cell responses to chemotherapy through the interactions between leukemia cells and the stroma, and show that a combination of galectin-3 inhibition with conventional drugs can sensitize the leukemia cells to chemotherapy.

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Low molecular weight B cell growth factor induces proliferation of human B cell precursor acute lymphoblastic leukemias

Blood ◽

10.1182/blood.v70.1.132.bloodjournal701132 ◽

1987 ◽

Vol 70 (1) ◽

pp. 132-138 ◽

Cited By ~ 1

Author(s):

B Wormann ◽

SR Mehta ◽

AL Maizel ◽

TW LeBien

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Growth Factor ◽

Cell Growth ◽

B Cell ◽

Lymphoblastic Leukemia ◽

Leukemic Cells ◽

Cell Precursor ◽

B Cell Growth Factor ◽

B Cell Precursors

Experiments were conducted to determine the effect of low mol wt B cell growth factor (L-BCGF) on B cell precursor acute lymphoblastic leukemia (ALL). L-BCGF induced a significant increase in 3H-TdR incorporation in 28 of 37 bone marrow aspirates from patients with B cell precursor ALL, with stimulation indices ranging from 2 to 129. Fluorescence-activated cell sorting confirmed that in five of seven patients the common acute lymphoblastic leukemia antigen (CALLA)/CD10 positive leukemic cells were responding directly to L-BCGF. L-BCGF was capable of inducing, in some patients, an increase in absolute viable cells and could also induce colony formation in vitro. The response of B cell precursor ALL was not attributable to beta IL 1, IL 2, or gamma interferon. These results indicate that the majority of B cell precursor ALL undergo a proliferative response to L-BCGF, suggesting a regulatory role for this lymphokine in the growth of B cell precursors.

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