title: Regeneration-associated WNT signaling is activated in long-term reconstituting AC133bright acute myeloid leukemia cells.
abstract: Acute myeloid leukemia (AML) is a genetically heterogeneous clonal disorder characterized by two molecularly distinct self-renewing leukemic stem cell (LSC) populations most closely related to normal progenitors and organized as a hierarchy. A requirement for WNT/β-catenin signaling in the pathogenesis of AML has recently been suggested by a mouse model. However, its relationship to a specific molecular function promoting retention of self-renewing leukemia-initiating cells (LICs) in human remains elusive. To identify transcriptional programs involved in the maintenance of a self-renewing state in LICs, we performed the expression profiling in normal (n = 10) and leukemic (n = 33) human long-term reconstituting AC133(+) cells, which represent an expanded cell population in most AML patients. This study reveals the ligand-dependent WNT pathway activation in AC133(bright) AML cells and shows a diffuse expression and release of WNT10B, a hematopoietic stem cell regenerative-associated molecule. The establishment of a primary AC133(+) AML cell culture (A46) demonstrated that leukemia cells synthesize and secrete WNT ligands, increasing the levels of dephosphorylated β-catenin in vivo. We tested the LSC functional activity in AC133(+) cells and found significant levels of engraftment upon transplantation of A46 cells into irradiated Rag2(-/-)γc(-/-) mice. Owing to the link between hematopoietic regeneration and developmental signaling, we transplanted A46 cells into developing zebrafish. This system revealed the formation of ectopic structures by activating dorsal organizer markers that act downstream of the WNT pathway. In conclusion, our findings suggest that AC133(bright) LSCs are promoted by misappropriating homeostatic WNT programs that control hematopoietic regeneration.
authors: Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milano, Italy. alessandro.beghini@unimi.it
authors: Alessandro
authors: A
authors: Beghini
authors: Francesca
authors: F
authors: Corlazzoli
authors: Luca
authors: L
authors: Del Giacco
authors: Matteo
authors: M
authors: Re
authors: Francesca
authors: F
authors: Lazzaroni
authors: Matteo
authors: M
authors: Brioschi
authors: Giorgio
authors: G
authors: Valentini
authors: Fulvia
authors: F
authors: Ferrazzi
authors: Anna
authors: A
authors: Ghilardi
authors: Marco
authors: M
authors: Righi
authors: Mauro
authors: M
authors: Turrini
authors: Marco
authors: M
authors: Mignardi
authors: Clara
authors: C
authors: Cesana
authors: Vincenzo
authors: V
authors: Bronte
authors: Mats
authors: M
authors: Nilsson
authors: Enrica
authors: E
authors: Morra
authors: Roberto
authors: R
authors: Cairoli
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D006023:Glycoproteins / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D010766:Phosphorylation; D061251:Primary Cell Culture; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration / Q000235:genetics*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000235:genetics*; D015027:Zebrafish; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D011518:Proto-Oncogene Proteins; C491119:WNT10B protein, human; D051153:Wnt Proteins; D051176:beta Catenin