The emerging role of Wnt signaling in the pathogenesis of acute myeloid leukemia

Abstract

Wnt signaling plays an important role in stem cell self-renewal and proliferation. Aberrant activation of Wnt signaling and its downstream targets are intimately linked with several types of cancer with colon cancer being the best-studied example. However, recent results also suggest an important role of Wnt signaling in normal as well as leukemic hematopoietic stem cells. Aberrant activation of Wnt signaling and downstream effectors has been demonstrated in acute myeloid leukemia. Here, mutant receptor tyrosine kinases, such as Flt3 and chimeric transcription factors such as promyelocytic leukemia-retinoic acid receptor-a and acute myeloid leukemia1-ETO, induce downstream Wnt signaling events. These findings suggest that the Wnt signaling pathway is an important target in several leukemogenic pathways and may provide a novel opportunity for targeting leukemic stem cells.

The role of sirtuin 2 activation by nicotinamide phosphoribosyltransferase in the aberrant proliferation and survival of myeloid leukemia cells

“…The dephosphorylated (active) form of GSK3β promotes β-catenin degradation by phosphorylating β-catenin on Ser33/37. 22,23 Consistent with the known activation of β-catenin in AML blasts, 27,32 we found that the levels of nuclear β-catenin were elevated in blasts of a selected AML patient ( Figure 5A). We, therefore, analyzed whether NAMPT or SIRT2 inhibition resulted in increased phosphorylation of β-catenin.…”

“…24 Active nuclear β-catenin has been detected in blasts of myeloid leukemia patients as well as in patients with other hematologic malignancies. [27][28][29][30][31][32][33] Interestingly, we demonstrated that inhibition of SIRT2 or NAMPT resulted in dephosphorylation/activation of GSK3β and subsequent phosphorylation/deactivation of β-catenin, which is the first step in β-catenin degradation. Because inhibition of either SIRT2 or NAMPT induced dephosphorylation/inactivation of AKT, this process is most likely AKT-dependent.…”

“…24 β-catenin induces proliferation and survival, but inhibits differentiation of hematopoietic stem cells (HSC). [25][26][27][28] Hyperactivated β-catenin has been described in various hematologic malignancies, such as acute and chronic myeloid leukemia, chronic lymphocytic leukemia, B-cell neoplasia and multiple myeloma. [27][28][29][30][31][32] Here, we aimed to evaluate the involvement of NAMPT and SIRT2 in the aberrant proliferation and survival of leukemic cells, and to ascertain whether the AKT/GSK3β/β-catenin signaling pathway plays a role in mediating this process.…”

Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy

“…172 This may occur due to mutations in Flt-3 and chimeric transcription factors such as promyelocytic leukemia gene fused to the Promyelocytic leukemia-retinoic acid receptor-a gene (PML-RARa) and AML-ETO. ITDs of the Flt-3 gene have been detected in leukemia stem cells.…”

Upsides and downsides to polarity and asymmetric cell division in leukemia

“…The Wnt-regulated transcription factor, LEF1, is overexpressed in human leukemias, and constitutive activation of LEF1 in mice leads to B-cell lymphoblastic leukemia and acute myeloid leukemia (AML) (Petropoulos et al, 2008). A number of observations suggest that Wnt is important in AML and chronic lymphocytic leukemia (Lu et al, 2004;Mikesch et al, 2007), and abnormal methylation of Wnt pathway components is associated with poor prognosis in ALL patients (Roman-Gomez et al, 2007). The central mediator of the Wnt canonical signaling pathway is the cytosolic protein b-catenin, which clearly has a function in leukemia.…”