KDM2b/JHDM1b, an H3K36me2-specific demethylase, is required for initiation and maintenance of acute myeloid leukemia

Abstract

The histone H3 lysine 36 dimethylspecific demethylase KDM2b/JHDM1b, which is highly expressed in various human leukemias, was previously found to be important in regulating cell proliferation and cellular senescence. However, its functions in leukemia development and maintenance are unclear. Here, we demonstrate that ectopic expression of IntroductionPrevious studies have shown that human leukemic cells from the same patient are composed of heterogeneous cell populations with various proliferation capacities and differentiation status. In the proposed leukemia stem cell (LSC) model, a fraction of LSCs resides at the apex of leukemia cellular hierarchy. Similar to hematopoietic stem cells (HSCs) in normal blood development, LSCs can give rise to the entire cellular hierarchy and sustain leukemia expansion through an unlimited self-renewal capability. 1 This model is supported by studies in which LSC-enriched cell populations, such as the CD34 ϩ CD38 Ϫ leukemic cells in human acute myeloid leukemia (AML), transplanted into SCID mice are able to fully recapitulate the process of leukemia development. 2,3 LSCs can be derived from different cellular compartments according to the leukemia type and disease stage. In a Junb inactivation-induced chronic myeloid leukemia (CML) murine model, the CML-like disease can only develop from Junbinactivated HSCs but not progenitor cells, indicating that LSCs may derive from HSCs. 4 However, in the accelerated and myeloid blast crisis phases of human CML, only leukemic granulocytemacrophage progenitors can be expanded and display an aberrant self-renewing capacity in vitro in the methylcellulose replating assay. 5 In addition, the fact that certain murine AMLs can be induced by retroviral transduction of oncogenes, such as Mll fusion genes, into the granulocyte-macrophage progenitor population indicates that LSCs can originate from committed progenitor cells directly. 6,7 These studies suggest that the "stemness" program of LSCs could be activated by various oncogenic stimuli in different cellular contexts. However, the molecular mechanisms underlying LSC self-renewal is not well understood. 8 The leukemic stem cell model implies that epigenetic regulation at certain critical gene loci might be important in determining the phenotypic difference between self-renewing LSCs and their non-self-renewing progeny. 8 One example that supports this notion comes from the demonstration that the Ink4a-Arf-Ink4b locus, which encodes 3 tumor suppressors, including p16 Ink4a , p15 Ink4b , and p19 Arf is controlled by the Polycomb repressive complex 1 (PRC1) in both normal HSCs and LSCs. 9,10 Biochemical analysis has shown that the PRC1 complex contains an ubiquitin E3 ligase activity and catalyzes the monoubiquitylation of histone H2A at lysine 119, which may serve as an epigenetic mark for the recruitment of other transcriptional repressors to the Ink4a-ArfInk4b locus. 11,12 Consistently, deletion of BMI-1, a component of the PRC1 complex, in LSCs leads to de-repression of Ink4a-Arf expression...

Fbxl10 overexpression in murine hematopoietic stem cells induces leukemia involving metabolic activation and upregulation of Nsg2

“…12 Furthermore, another study demonstrated that the demethylase enzymatic activity was required for leukemic transformation in a Hoxa9-Meis1-induced mouse BM transplantation model. 13 These findings suggest that Fbxl10 contributes to the development of tumor in vivo. The online version of this article contains a data supplement.…”

“…Previous studies have reported that Fbxl10 suppresses senescenceassociated cyclin-dependent kinase inhibitors (CDKIs) such as p15ink4b, p16ink4a, p18ink4c, and p57kip2 in murine blood cells. 12,13 Therefore, we investigated the possibility that suppression of these CDKI genes might account for the survival/proliferation advantage in Tg HSCs, which is reminiscent of the canonical class I mutations. The former 2 genes, p15ink4b and p16ink4a, were very weakly expressed in primary control HSCs, as reported in a previous transcriptome analysis 22 ; no expressional change of these genes was observed in Tg HSCs.…”

Chromatin proteins and modifications as drug targets

“…For instance, members of the JMJD2/KDM4 family, which can demethylate H3K9me3/me2 and H3K36me3/me2, have been found overexpressed in squamous cell carcinoma, breast cancer, and medulloblastoma 47--49 . Moreover members of the JARID1/KDM5 family that demethylate H3K4me3/me2 are overexpressed in breast and bladder cancers 50,51 , and FBXL10/KDM2B, specific for H3K36me3/me2, is overexpressed in leukaemia 52 . Somatic mutations and deletions have also been identified in the JmjC--domain containing demethylases, including the H3K27me3/me2 demethylase UTX/KDM6A that is found mutated in for instance multiple myeloma and renal cell carcinoma 27,28 , and in JARID1C/KDM5C and PHF8 in X--linked mental retardation patients 53,54 .…”

T cell proliferation and adaptive immune responses are critically regulated by protein phosphatase 4

“…Oligonucleotide sequences are listed in Table S1, including the Ink4 family primers. 47 PCR thermocycler conditions are available upon request.…”