Mutant EZH2 contributes to lymphomagenesis partly by repressing and/or are frequently found in patients with MDS and myeloproliferative neoplasms (MPN). outcomes. (knockout mice showed a significantly lower frequency of hematopoietic stem cells (HSCs) due to impaired self-renewal . In addition, the forced Cycloguanil hydrochloride expression of Bmi1 enhanced the self-renewal of HSCs . Bmi1 also suppresses the commitment and differentiation of HSCs into B cells by repressing and and in HSCs and multipotent progenitors (MPPs), which was accompanied by accelerated lymphoid specification and a marked reduction in HSC/MPPs . Bmi1 is also required Cycloguanil hydrochloride to maintain leukemic stem cells as well as normal HSCs . The functions of EZH1 and EZH2 in hematopoiesis have also been well characterized. in adult mice impaired the self-renewal capacity of HSCs through de-repression of , while HSCs in and double knockout mice completely lost repopulation capacity . With respect to other PRC2 components, loss of Eed impaired differentiation of HSCs and led to HSC exhaustion . Suz12 has also been shown to be required for the maintenance of HSC . Several studies have revealed the physiological roles of PRC1.1 in hematopoiesis. KDM2B binds to nonmethylated CpG islands through its zinc finger-CxxC (ZF-CxxC) DNA-binding domain, thereby recruiting other components of PRC1.1. prevented exhaustion of the long-term repopulating potential of HSCs following serial transplantation . BCOR, a co-repressor of BCL6, played an important role in restricting differentiation toward the myeloid lineage, partly by repressing Rabbit Polyclonal to ATG16L2 and family genes. As a consequence, knockout mice showed myeloid-skewed differentiation [18,19]. Depletion of PCGF1 also led to myeloid-skewing  and de-repressed expression of family genes . Taken altogether, these data show that PRC1.1 regulates the functions of HSCs and restricts their differentiation toward the myeloid lineage by repressing the Cycloguanil hydrochloride transcription of genes required for myeloid differentiation, such as and family genes. 3. Functions of PRCs in Hematologic Malignancies Dysregulated function of epigenetic regulators is frequently involved in the pathogenesis of solid and hematological malignancies. PRCs play a pivotal role in the maintenance of HSCs and hematopoiesis, and dysregulation of PRC function has been implicated in the pathogenesis of hematological malignancies. Overexpression of PcG genes generally promotes tumorigenesis, partly through their ability to transcriptionally repress tumor suppressor genes, such as the locus (encoding p16INK4A and p14ARF), and developmental regulator genes . The expression of has correlated with disease progression and the prognosis of myelodysplastic syndrome (MDS) , the prognoses of acute myeloid leukemia (AML) and chronic myeloid Cycloguanil hydrochloride leukemia . In contrast, loss-of-function mutations in PRC genes, such as and are of particular interest owing Cycloguanil hydrochloride to their relatively high frequencies, pathological significance, and potential as therapeutic targets. Table 1 Frequencies of mutations in PRC genes in hematologic malignancies. is frequently overexpressed and/or amplified in prostate, breast, bladder, and colon cancers , and its expression is correlated with metastasis  and poor prognosis [54,55]. We and other groups have shown that Ezh2 exerts an oncogenic function during the maintenance phase of MLL-AF9 AML in mice and could be therapeutically targeted. In contrast, Ezh2 acts as a tumor suppressor during the induction phase of AML [56,57,58]. EZH2 is strongly expressed in germinal center (GC) B cells and acts with BCL6 to recruit a noncanonical PRC1-BCOR complex containing CBX8 in a GC B-cellCspecific manner to repress the expression of differentiation genes . Correspondingly, gain-of-function mutations in are frequently found in GC B-cellCtype lymphoma  in which H3K27me3 levels are significantly elevated . Mutant EZH2 contributes to lymphomagenesis partly by repressing and/or are frequently found in patients with MDS and myeloproliferative neoplasms (MPN). Although mutations are rare in de novo AML patients, they are frequently found in patients with secondary AML transformed from.