**6.2 LSCs-related signaling pathways**

Leukemia is characterized by selective overgrowth of LSCs and interferes with 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 and inducing leukemia [91].

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 safety and efficacy in humans.

#### **Figure 2.**

*The niche of leukemic stem cell. The niche provides support for self-renewal, quiescence, homing, engraftment, and proliferative potential for HSCs. LSCs may impair the function of the normal HSC niche. In addition, LSCs can infiltrate these niches and may hijack these normal homeostatic processes.*
