Advances in understanding leukemia bone marrow microenvironments / 药学学报

The bone marrow microenvironment, also known as the bone marrow niche, plays a critical role in maintaining the functions of hematopoietic stem cells. Under physiological conditions, various bone marrow cells regulate each other to sustain hematopoietic homeostasis. However, bone marrow cells gain abnormal function under pathological conditions to cause and promote the occurrence of leukemia and induce drug resistance. Recent findings indicate that abnormal proliferation and differentiation are not the sole reason to cause leukemia. Different types of bone marrow cells also induce intercellular adhesion, abnormally secrete cytokines and chemokines, accelerating leukemia's progress. This article reviews the multiple signaling pathways that regulate the formation and progress of leukemia bone marrow niche, such as C-X-C motif chemokine ligand 12/C-X-C motif chemokine receptor 4 signaling pathway, et al. It emphasizes that targeting leukemia bone marrow niche is a vital strategy for improving the leukemia treatment.

TRIB3 promotes B-ALL progression by suppressing CTSZ-mediated BCR-ABL degradation / 药学学报

Philadelphia chromosome (Ph) positive (Ph+) B cell acute lymphoblastic leukemia (B-ALL) is the most common genetic abnormality associated with B-ALL and has been shown to confer the worst prognosis to both children and adults. Increasing evidence has revealed that high tribbles homologue 3 (TRIB3) expression contributes to multi-cancer development and progression, but the underlying role and molecular mechanisms of TRIB3 in Ph+ B-ALL remain unclear. Here, we report that TRIB3 expression was enhanced in Ph+ B-ALL patient samples and positively associated with the expression of breakpoint cluster region-Abelson tyrosine kinase (BCR-ABL). We further demonstrated that deletion of TRIB3 attenuated the progression of Ph+ B-ALL by reducing BCR-ABL expression. Mechanistically, TRIB3 interacted with lysosomal cysteine proteinase cathepsin Z (CTSZ) to suppress CTSZ-mediated BCR-ABL degradation, which enhanced BCR-ABL activity, causing high proliferation of Ph+ B-ALL cells. Thus, our study indicated that inhibiting the expression of TRIB3 to regulate BCR-ABL kinase activity may be exploited as an additional target therapy for Ph+ ALL. Procedures for animal study were performed with approval of the Animal Care and Use Committee of the Chinese Academy of Medical Sciences and Peking Union Medical College. The procedure of human leukemia sample was approved by the Ethics Committee of Chinese Academy of Medical Sciences and Peking Union Medical College (KT2019055-EC-1).