Abstract
Transforming growth factor-β (TGF-β) signaling plays diverse roles in regulating cell proliferation, differentiation, and “stemness” in a cell context-dependent manner. In the first section of this chapter, we outline the genetic changes that attenuate TGF-β signaling in patients with acute myelogenous leukemia (AML), or the blast crisis phase of chronic myelogenous leukemia (CML), or pediatric acute lymphoblastic leukemia (ALL). In the second section, we discuss recent advances in stem cell research indicating that TGF-β signaling does not always suppress leukemogenesis. In fact, TGF-β signaling paradoxically sustains the survival and resistance to therapy of the CML stem cells that are responsible for disease recurrence in CML patients treated with tyrosine kinase inhibitors (TKIs). We examine evidence implicating TGF-β and its downstream effectors Akt and FOXO in the in vivo maintenance of the self-renewal ability of both TKI-resistant CML stem cells and the normal hematopoietic stem cells (HSCs) from which they are derived. Increased knowledge of the complex effects of TGF-β signaling may lead to improved diagnostic and therapeutic tools that can benefit leukemia patients.
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Abbreviations
- ALL:
-
Acute lymphoblastic leukemia
- AML:
-
Acute myelogenous leukemia
- ANLL:
-
Acute nonlymphoblastic leukemia
- APL:
-
Acute promyelocytic leukemia
- ATRA:
-
All-trans retinoic acid
- BMP:
-
Bone morphogenetic protein
- Bmpr1a:
-
BMP receptor type 1A
- CCyR:
-
Complete cytogenetic response
- CML:
-
Chronic myelogenous leukemia
- cPML:
-
Cytoplasmic isoform of PML
- FAB:
-
French–American–British
- GFAP:
-
Glial fibrillary acidic protein
- HSC:
-
Hematopoietic stem cell
- KIR:
-
Killer immunoglobulin-like receptor
- L-GMP:
-
Leukemic-granulocyte-macrophage progenitor
- LRC:
-
Lipid raft clustering
- LSK:
-
Lineage−Sca-1+c-Kit+
- MEF:
-
Mouse embryonic fibroblast
- MPN:
-
Myeloproliferative neoplasm
- NK:
-
Natural killer
- PI3K:
-
Phosphatidylinositol-3-OH kinase
- PML:
-
Promyelocytic leukemia
- RARα:
-
Retinoic acid receptor α
- ROS:
-
Reactive oxygen species
- SARA:
-
Smad anchor for receptor activation
- SCL:
-
Stem cell leukemia
- SOD:
-
Superoxide dismutase
- TGF-β:
-
Transforming growth factor-β
- TKI:
-
Tyrosine kinase inhibitor
- WHO:
-
World Health Organization
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Naka, K., Hirao, A. (2013). TGF-β Signaling in Leukemogenesis. In: Moustakas, A., Miyazawa, K. (eds) TGF-β in Human Disease. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54409-8_8
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