Integrin-α9 overexpression underlies the niche-independent maintenance of leukemia stem cells in acute myeloid leukemia.

Leukemia stem cells (LSCs) are widely believed to reside in well-characterized bone marrow (BM) niches; however, the capacity of the BM niches to accommodate LSCs is insufficient, and a significant proportion of LSCs are instead maintained in regions outside the BM. The molecular basis for this niche-independent behavior of LSCs remains elusive. Here, we show that integrin-α9 overexpression (ITGA9 OE) plays a pivotal role in the extramedullary maintenance of LSCs by molecularly mimicking the niche-interacting status, through the binding with its soluble ligand, osteopontin (OPN).

Epigenetic dysregulation of eukaryotic initiation factor 3 subunit E (eIF3E) by lysine methyltransferase REIIBP confers a pro-inflammatory phenotype in t(4;14) myeloma.

REIIBP is a lysine methyltransferase aberrantly expressed through alternative promoter usage of NSD2 locus in t(4;14)-translocated multiple myeloma (MM). Clinically, t(4;14) translocation is an adverse prognostic factor found in approximately 15% of MM patients. The contribution of REIIBP relative to other NSD2 isoforms as a dependency gene in t(4;14)-translocated MM remains to be evaluated.

Histone Methyltransferase NSD2 Activates PKCα to Drive Metabolic Reprogramming and Lenalidomide Resistance in Multiple Myeloma.

Unlabelled: Multiple myeloma cells undergo metabolic reprogramming in response to the hypoxic and nutrient-deprived bone marrow microenvironment. Primary oncogenes in recurrent translocations might be able to drive metabolic heterogeneity to survive the microenvironment that can present new vulnerabilities for therapeutic targeting. t(4;14) translocation leads to the universal overexpression of histone methyltransferase NSD2 that promotes plasma cell transformation through a global increase in H3K36me2.

Super Enhancer-Mediated Upregulation of Promotes Growth and Survival of t(4;14)-Positive Multiple Myeloma.

Multiple myeloma is an incurable malignancy with marked clinical and genetic heterogeneity. The cytogenetic abnormality t(4;14) (p16.3;q32.

Identification of differential RNA modifications from nanopore direct RNA sequencing with xPore.

RNA modifications, such as N-methyladenosine (mA), modulate functions of cellular RNA species. However, quantifying differences in RNA modifications has been challenging. Here we develop a computational method, xPore, to identify differential RNA modifications from nanopore direct RNA sequencing (RNA-seq) data.

Determinants of response to daratumumab in Epstein-Barr virus-positive natural killer and T-cell lymphoma.

Background: The potential therapeutic efficacy of daratumumab in natural killer T-cell lymphoma (NKTL) was highlighted when its off-label usage produced sustained remission in a patient with highly refractory disease. This is corroborated recently by a phase II clinical trial which established that daratumumab monotherapy is well tolerated and displayed encouraging response in relapsed/refractory NKTL patients. However, little is known regarding the molecular factors central to the induction and regulation of the daratumumab-mediated antitumor response in NKTL.

SMARCA2 Is a Novel Interactor of NSD2 and Regulates Prometastatic through Chromatin Remodeling in t(4;14) Multiple Myeloma.

NSD2 is the primary oncogenic driver in t(4;14) multiple myeloma. Using SILAC-based mass spectrometry, we demonstrate a novel role of NSD2 in chromatin remodeling through its interaction with the SWI/SNF ATPase subunit SMARCA2. SMARCA2 was primarily expressed in t(4;14) myeloma cells, and its interaction with NSD2 was noncanonical and independent of the SWI/SNF complex.

Myeloma-specific superenhancers affect genes of biological and clinical relevance in myeloma.

Multiple myeloma (MM) is an aggressive plasma cell neoplasm characterized by genomic heterogeneity. Superenhancers (SEs) are defined as large clusters of enhancers in close genomic proximity, which regulate genes for maintaining cellular identity and promote oncogenic transcription to which cancer cells highly addicted. Here, we analyzed cis-regulatory elements in MM samples with H3K27ac ChIP-seq, to identify novel SE-associated genes involved in the myeloma pathogenesis.

ASLAN003, a potent dihydroorotate dehydrogenase inhibitor for differentiation of acute myeloid leukemia.

Differentiation therapies achieve remarkable success in acute promyelocytic leukemia, a subtype of acute myeloid leukemia. However, excluding acute promyelocytic leukemia, clinical benefits of differentiation therapies are negligible in acute myeloid leukemia except for mutant isocitrate dehydrogenase 1/2. Dihydroorotate dehydrogenase catalyses the fourth step of the de novo pyrimidine synthesis pathway.

IL6 Promotes a STAT3-PRL3 Feedforward Loop via SHP2 Repression in Multiple Myeloma.

Overexpression of PRL-3, an oncogenic phosphatase, was identified as a novel cluster in patients with newly diagnosed multiple myeloma. However, the regulation and oncogenic activities of PRL-3 in multiple myeloma warrant further investigation. Here, we report that IL6 activates STAT3, which acts as a direct transcriptional regulator of PRL-3.

MMSET I acts as an oncoprotein and regulates GLO1 expression in t(4;14) multiple myeloma cells.

Multiple myeloma (MM) is characterized by recurrent chromosomal translocations. T(4;14) MM overexpresses multiple myeloma SET domain-containing protein (MMSET). MMSET has three major isoforms: the full-length form MMSET II and the short isoforms REIIBP and MMSET I.

Non-canonical activation of β-catenin by PRL-3 phosphatase in acute myeloid leukemia.

Aberrant activation of Wnt/β-catenin signaling pathway is essential for the development of AML; however, the mechanistic basis for this dysregulation is unclear. PRL-3 is an oncogenic phosphatase implicated in the development of LSCs. Here, we identified Leo1 as a direct and specific substrate of PRL-3.

Aberrant hyperediting of the myeloma transcriptome by ADAR1 confers oncogenicity and is a marker of poor prognosis.

DNA alterations have been extensively reported in multiple myeloma (MM); however, they cannot yet fully explain all the biological and molecular abnormalities in MM, which remains to this day an incurable disease with eventual emergence of refractory disease. Recent years have seen abnormalities at the RNA levels being reported to possess potential biological relevance in cancers. ADAR1-mediated A-to-I editing is an important posttranscriptional mechanism in human physiology, and the biological implication of its abnormality, especially at the global level, is underexplored in MM.

NF-κB promotes the stem-like properties of leukemia cells by activation of LIN28B.

Aim: To examine whether nuclear factor kappa B (NF-κB) activity regulates LIN28B expression and their roles in leukemia stem cell (LSC)-like properties.

Methods: We used pharmacological inhibitor and cell viability assays to examine the relation between NF-κB and LIN28B. Western blot and qRT-PCR was employed to determine their protein and mRNA levels.

A loss-of-function genetic screening reveals synergistic targeting of AKT/mTOR and WTN/β-catenin pathways for treatment of AML with high PRL-3 phosphatase.

Background: Protein tyrosine phosphatase of regenerating liver 3 (PRL-3) is overexpressed in a subset of AML patients with inferior prognosis, representing an attractive therapeutic target. However, due to relatively shallow pocket of the catalytic site of PRL-3, it is difficult to develop selective small molecule inhibitor.

Methods: In this study, we performed whole-genome lentiviral shRNA library screening to discover synthetic lethal target to PRL-3 in AML.

Inhibition of LIN28B impairs leukemia cell growth and metabolism in acute myeloid leukemia.

Background: Current conventional chemotherapy for acute myeloid leukemia (AML) can achieve remission in over 70% of patients, but a majority of them will relapse within 5 years despite continued treatment. The relapse is postulated to be due to leukemia stem cells (LSCs), which are different from normal hematopoietic stem cells (HSCs). LIN28B is microRNA regulator and stem cell reprogramming factor.

LIN28B Activation by PRL-3 Promotes Leukemogenesis and a Stem Cell-like Transcriptional Program in AML.

PRL-3 (PTP4A3), a metastasis-associated phosphatase, is also upregulated in patients with acute myeloid leukemia (AML) and is associated with poor prognosis, but the underlying molecular mechanism is unknown. Here, constitutive expression of PRL-3 in human AML cells sustains leukemogenesis and Furthermore, PRL-3 phosphatase activity dependently upregulates LIN28B, a stem cell reprogramming factor, which in turn represses the let-7 mRNA family, inducing a stem cell-like transcriptional program. Notably, elevated levels of LIN28B protein independently associate with worse survival in AML patients.

PRIMA-1met (APR-246) inhibits growth of colorectal cancer cells with different p53 status through distinct mechanisms.

PRIMA-1met (APR-246) is a methylated derivative and structural analog of PRIMA-1 (p53 re-activation and induction of massive apoptosis). PRIMA-1met has been reported to restore both the wild type (wt) structure and function of mutant p53. Here, we show that PRIMA-1met is highly effective at limiting the growth of CRC cells regardless of p53 status.

Disruption of Runx1 and Runx3 leads to bone marrow failure and leukemia predisposition due to transcriptional and DNA repair defects.

The RUNX genes encode transcription factors involved in development and human disease. RUNX1 and RUNX3 are frequently associated with leukemias, yet the basis for their involvement in leukemogenesis is not fully understood. Here, we show that Runx1;Runx3 double-knockout (DKO) mice exhibited lethal phenotypes due to bone marrow failure and myeloproliferative disorder.