Regulation of myeloid leukaemia by the cell-fate determinant Musashi

Abstract

Chronic myelogenous leukemia (CML) can progress from an indolent chronic phase to an aggressive blast crisis phase1 but the molecular basis of this transition remains poorly understood. Here we have used mouse models of CML2,3 to show that disease progression is regulated by the Musashi-Numb signaling axis4,5. Specifically, we find that chronic phase is marked by high and blast crisis phase by low levels of Numb expression, and that ectopic expression of Numb promotes differentiation and impairs advanced phase disease in vivo. As a possible explanation for the decreased levels of Numb in blast crisis, we show that NUP98-HOXA9, an oncogene associated with blast crisis CML6,7, can trigger expression of the RNA binding protein Musashi2 (Msi2) which in turn represses Numb. Importantly, loss of Msi2 restores Numb expression and significantly impairs the development and propagation of blast crisis CML in vitro and in vivo. Finally, we show that Msi2 expression is not only highly upregulated during human CML progression but is also an early indicator of poorer prognosis. These data show that the Musashi-Numb pathway can control the differentiation of CML cells, and raise the possibility that targeting this pathway may provide a new strategy for therapy of aggressive leukemias.

Stem cell maintenance and disease progression in chronic myeloid leukemia

“…Genetic loss of Msi2 results in increased Numb levels and, as a consequence, functionally impairs the development and propagation of BC-CML in vivo. Interestingly, Msi2 is not only highly upregulated during human CML progression, but is also a marker for poorer prognosis in human BC-CML and de novo AMLs [57,58]. Collectively, these studies define the essential role of the RNA binding factor Msi2 as a molecular driver of cancer progression by regulating the balance between stem cell self-renewal and differentiation.…”

“…Msi1 inactivation alone results in barely appreciable defects during embryonic neural development, which may be due to functional redundancies among the two paralogs [56]. The second gene, Msi2, is predominantly expressed in the most immature HSC compartment within the hematopoietic organ, and during CML disease progression, Msi2 expression levels are significantly elevated in the blast crisis phase [57]. Importantly, NUP98-HOXA9 can trigger Msi2 expression, which in turn represses Numb expression.…”

New insight into cancer therapeutics: Induction of differentiation by regulating the Musashi/Numb/Notch pathway

“…Based on the evidence that tissue stem cells exist in many adult tissues, including the hematopoietic system, intestine, mammary gland, testis, skeletal muscle, skin, hair follicle and myocardium, other than the CNS and neural crest-derived tissue, Msi/Numb/Notch signaling is considered to be associated with many adult malignancies [2]. In fact, not only at the normal developmental stages, the Msi-signaling pathway is also reported to work during tumorigenesis in several adult tissues, including glioblastoma and esophageal, colon, pulmonary, mammary and bladder carcinomas [2,[10][11][12][13]. Intriguingly, in the case of esophageal adenocarcinoma, Msi1 expression was the highest in glands during early cancer development.…”

“…Although a previous report showed that Msi2 gene was rearranged to form a Msi2/HoxA9 fusion gene in a chronic myeloid leukemia (CML) case with the 7p15 breakpoint [14], the recent papers reported by Ito et al [12] and Kharas et al [13] were the first reports to show clearly the relationship between Msi2-inducing pathway and hematopoietic malignancy. These two reports suggested a new strategy for the therapy of aggressive leukemia.…”

The Human MSI2 Gene is Associated with Schizophrenia in the Chinese Han Population

“…So, apart from its role in neural stem cells and neuronal development, MSI2 may be involved in the maintenance of proper functioning of PV-containing GABAergic interneurons by controlling the local translation or stability of mRNAs that encode essential neurotransmitters, receptors, and channels. MSI2 is also expressed in the stem-cell compartments of other tissues and in aggressive tumors as well as playing a broad role in stemness and the determination of cell fate [35][36][37][38][39]. The detailed action of MSI2 on physiological and pathological processes requires further research.…”