**5.2 NF-κB pathway**

NF-κB is a significant transcriptional activator located upstream of the IRF-1 gene. It is aberrantly activated by LSCs. NF-κB not only inhibits apoptosis but also regulating the expression of cytokine genes. Furthermore, apoptosis can be inhibited by inducing and upregulating antiapoptotic genes. Therefore, NF-κB plays an essential role in maintaining LSC growth and survival. Inhibition of this signaling pathway not only promotes LSC apoptosis but also enhances the sensitivity of LSCs to chemotherapeutic drugs [74, 75]. At present, the targeted drugs for NF-κB are mainly proteasome inhibitors MG-132 and Bortezomib (VELCADE, PS-341), which can better target LSCs without any significant effect on normal HSC. It was reported that PTL can specifically induce apoptosis of LSCs by inhibiting NF-κB activity. At present, the PTL analog DMAP has been developed, and its experimental effect is remarkable [76, 77].

### **5.3 PI3K/Akt pathway**

The PI3K/Akt pathway is an intracellular pathway that plays a critical role in apoptosis and cancer, whose components are often altered in cancer, leading to dysregulated apoptosis and chemoresistance [78]. Chen et al. demonstrated that the PI3K inhibitor LY294002 can directly target LSCs without adverse reactions to normal HSCs, and they found that PI3K and NF-κB may coexist in the same signaling pathway [79]. Further, it has been reported that the mammalian target of rapamycin (mTOR) is a substrate for PI3K that regulates the survival of LCSs after etoposide treatment. Mise et al. showed that the inhibitory effect of rapamycin on mTOR significantly reduced the survival rate of AML cells, and rapamycin enhanced the effect of etoposide on these cells [80]. It is found that PTEN that negatively regulates the PI3K pathway and is essential for maintaining normal hematopoiesis [81]. However, PTEN deletion has no significant effect on HSC differentiation survival, while PTEN deletion in LSCs can lead to the production and proliferation of LSCs. In addition, rapamycin, an inhibitor of the PI3K pathway downstream regulator of mTOR was found to inhibit LSCs and protect against normal HSC failure.

**19**

*Advances in Acute Myeloid Leukemia Stem Cells DOI: http://dx.doi.org/10.5772/intechopen.84263*

Niche is involved in stem cell self-renewal, survival, chemotherapy tolerance, and metastasis of leukemia cells [82]. In the mice model, it was found that the homing of HSCs to the bone marrow is regulated by chemokine CXCL12 expressed in mesenchymal stem cells, and its receptor is CXCR4 [83]. Inhibition of CXCL12- CXCR4 interaction helps to reduce chemotaxis, thus affecting the movement, adhesion, and metastasis of LSCs. In vitro studies have shown that the anti-leukemia active peptide CXCR4 inhibitor LY2510924, as a single agent or in combination chemotherapy, can rapidly and permanently destroy the CXCL12-CXCR4 axis, thereby inhibiting the proliferation of AML cells and leading to apoptosis [84]. Fully human IgG4 monoclonal antibody BMS-936564 against CXCR4 showed high safety and antitumor activity in relapsed and refractory patients with AML [85]. However, because of the similar biological properties of LSCs and HSCs, the non-selection of

In addition to participating in the hematopoietic function, the bone marrow niche is also an important place for the presence of immune cells. There is a group of activated leukemia-specific immune cells in leukemia bone marrow, and regulatory T cell (Treg) is one of the important members [86]. Fujisaki et al. found that hematopoietic stem/progenitor cells and Treg can coexist on the endosteum of murine bone marrow, and HSPC disappears shortly after Treg cell depletion [87]. This experiment successfully demonstrated the involvement of Treg cells in the formation of bone marrow niche. Treg is a dynamic cell population that regulates the immune response. Stem cells evade immune surveillance by recruiting Treg cells and using their regulatory functions [88]. Therefore, it is speculated that these cells

Leukemia is characterized by selective overgrowth of LSCs and interferes with

In recent years, studies on micro-RNA and transcription factors in leukemia patients have become increasingly mature. For example, the transcription factor MYC can inhibit the expression of the shared target gene FLT3 by miR-15a-5p, and FLT3 plays a crucial role in activating the STAT5A pathway and promoting tumor cell proliferation [92, 93], but its specific mechanism of influence on the development of tumor remains to be further investigated. Targeted drugs in mounting numbers for LSCs signaling pathways are being developed, but most of them are still in the stage of animal experiments, and more research is needed to determine

the differentiation of HSCs. Chemotherapy kills rapidly dividing cancer cells, but does not eliminate reservoirs of LSCs that cause relapse. LSCs have a variety of regulatory abnormal signaling pathways, including WNT/β-catenin, JAK/ STAT, PI3K/AKT, RAS, NF-κB, and Notch. WNT is involved in the maintenance of properties of LSCs. Riether et al. discovered that tyrosine kinase inhibitors induced CD70 expression on LSCs during targeted drug therapy, while CD70 inhibited WNT/β-catenin signaling pathway [90]. STAT is an important transcription factor regulating cell growth, proliferation, and inhibition of apoptosis. Activation of the JAK/STAT signaling pathway is associated with sustained activation of the protooncogene AHI-1 in CD34 cells, regulating CML-LSC autonomous growth in vitro

related inhibitors has become another major clinical problem.

will likely become new targets for eliminating LSCs (**Figure 2**) [89].

**6.2 LSCs-related signaling pathways**

and inducing leukemia [91].

the safety and efficacy in humans.

**6. Treatment avenue for LSC**

**6.1 Niche of LSCs**
