The glycosyltransferase ST3GAL4 drives immune evasion in acute myeloid leukemia by synthesizing ligands for the glyco-immune checkpoint receptor Siglec-9.

Immunotherapy has demonstrated promise as a treatment for acute myeloid leukemia (AML). However, there is still an urgent need to identify new molecules that inhibit the immune response to AML. Most prior research in this area has focused on protein-protein interaction interfaces.

Emerging interactions between RNA methylation and chromatin architecture.

Epitranscriptomics, the study of chemical modifications of RNA molecules, is increasingly recognized as an important component of gene expression regulation. While the majority of research has focused on N-methyladenosine (mA) RNA methylation on mRNAs, emerging evidence has revealed that the mA modification extends beyond mRNAs to include chromatin-associated RNAs (caRNAs). CaRNAs constitute an important class of RNAs characterized by their interaction with the genome and epigenome.

mRNA-based therapeutic strategies for cancer treatment.

In the rapidly evolving landscape of medical research, the emergence of RNA-based therapeutics is paradigm shifting. It is mainly driven by the molecular adaptability and capacity to provide precision in targeting. The coronavirus disease 2019 pandemic crisis underscored the effectiveness of the mRNA therapeutic development platform and brought it to the forefront of RNA-based interventions.

Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis.

Protein synthesis is frequently deregulated during tumorigenesis. However, the precise contexts of selective translational control and the regulators of such mechanisms in cancer is poorly understood. Here, we uncovered CNOT3, a subunit of the CCR4-NOT complex, as an essential modulator of translation in myeloid leukemia.

A target discovery pipeline identified ILT3 as a target for immunotherapy of multiple myeloma.

Multiple myeloma (MM) is an incurable malignancy of plasma cells. To identify targets for MM immunotherapy, we develop an integrated pipeline based on mass spectrometry analysis of seven MM cell lines and RNA sequencing (RNA-seq) from 900+ patients. Starting from 4,000+ candidates, we identify the most highly expressed cell surface proteins.

RNA binding protein SYNCRIP maintains proteostasis and self-renewal of hematopoietic stem and progenitor cells.

Tissue homeostasis is maintained after stress by engaging and activating the hematopoietic stem and progenitor compartments in the blood. Hematopoietic stem cells (HSCs) are essential for long-term repopulation after secondary transplantation. Here, using a conditional knockout mouse model, we revealed that the RNA-binding protein SYNCRIP is required for maintenance of blood homeostasis especially after regenerative stress due to defects in HSCs and progenitors.

RNA modifications in hematological malignancies.

RNA modifications play an important role in various cancers including blood cancers by controlling gene expression programs critical for survival, proliferation and differentiation of cancer cells. While hundreds of RNA modifications have been identified, many have not been functionally characterized. With development of enabling technologies to identify and map RNA modifications, tremendous advancement has been made in our understanding of the biological functions of these molecular markers in diverse cellular contexts.

RNA deadenylation complexes in development and diseases.

RNA deadenylation, the process of shortening of the 3' poly(A) tail of an RNA molecule, is one of the key steps of post-transcriptional regulation of gene expression in eukaryotic cells. PAN2/3 and CCR4-NOT (CNOT) are the two dominant RNA deadenylation complexes, which play central roles in mediating mRNA decay and translation. While degradation is the final fate of virtually all RNAs in their life cycles, selection of RNA targets as well as control of the rate and timing of RNA decay, in coordination with other molecular pathways, including translation, can be modulated in certain contexts.

miR-148a-3p and DDX6 functional link promotes survival of myeloid leukemia cells.

Regulation of gene expression at the RNA level is an important regulatory mechanism in cancer. However, posttranscriptional molecular pathways underlying tumorigenesis remain largely unexplored. In this study, we uncovered a functional axis consisting of microRNA (miR)-148a-3p, RNA helicase DDX6, and its downstream target thioredoxin-interacting protein (TXNIP) in acute myeloid leukemia (AML).

mA RNA modifications: Key regulators of normal and malignant hematopoiesis.

Post-transcriptional RNA modifications determine RNA fate by influencing numerous processes such as translation, decay and localization. One of the most abundant RNA modifications is N-methyladenoside (mA), which has been shown to be important in healthy as well as malignant hematopoiesis. Several proteins representing key players in mA RNA biology, such as mA writers, erasers and readers, were recently reported to be essential for hematopoietic stem cell (HSC) function.

Transcriptional control of CBX5 by the RNA binding proteins RBMX and RBMXL1 maintains chromatin state in myeloid leukemia.

RNA binding proteins (RBPs) are key arbiters of post-transcriptional regulation and are found to be found dysregulated in hematological malignancies. Here, we identify the RBP RBMX and its retrogene RBMXL1 to be required for murine and human myeloid leukemogenesis. RBMX/L1 are overexpressed in acute myeloid leukemia (AML) primary patients compared to healthy individuals, and RBMX/L1 loss delayed leukemia development.

Introductions to the Community: Early-Career Researchers in the Time of COVID-19.

COVID-19 has unfortunately halted lab work, conferences, and in-person networking, which is especially detrimental to researchers just starting their labs. Through social media and our reviewer networks, we met some early-career stem cell investigators impacted by the closures. Here, they introduce themselves and their research to our readers.

HyperTRIBE uncovers increased MUSASHI-2 RNA binding activity and differential regulation in leukemic stem cells.

The cell-context dependency for RNA binding proteins (RBPs) mediated control of stem cell fate remains to be defined. Here we adapt the HyperTRIBE method using an RBP fused to a Drosophila RNA editing enzyme (ADAR) to globally map the mRNA targets of the RBP MSI2 in mammalian adult normal and malignant stem cells. We reveal a unique MUSASHI-2 (MSI2) mRNA binding network in hematopoietic stem cells that changes during transition to multipotent progenitors.

mA RNA Methylation Maintains Hematopoietic Stem Cell Identity and Symmetric Commitment.

Stem cells balance cellular fates through asymmetric and symmetric divisions in order to self-renew or to generate downstream progenitors. Symmetric commitment divisions in stem cells are required for rapid regeneration during tissue damage and stress. The control of symmetric commitment remains poorly defined.

The Biology of mA RNA Methylation in Normal and Malignant Hematopoiesis.

Hematopoietic development and differentiation are highly regulated processes, and recent studies focusing on mA mRNA methylation have uncovered how this mark controls cell fate in both normal and malignant hematopoietic states. In this review, we focus on how writers, readers, and erasers of RNA methylation can mediate distinct phenotypes on mRNAs and on cells. Targeting the RNA methylation program has emerged as a potential novel therapeutic strategy, and we explore the role for these regulators in both normal and dysregulated cell contexts.

Targeting the Residual Leukemia Cells after Chemotherapy.

One of the biggest challenges in treating acute myeloid leukemia (AML) is relapse of aggressive disease after treatment. In this issue of Cancer Cell, Boyd et al. characterize a molecularly distinct population of chemotherapy-induced transient leukemic regenerating cells (LRCs), which can be exploited to prevent AML recurrence.

The N-methyladenosine (mA)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells.

N-methyladenosine (mA) is an abundant nucleotide modification in mRNA that is required for the differentiation of mouse embryonic stem cells. However, it remains unknown whether the mA modification controls the differentiation of normal and/or malignant myeloid hematopoietic cells. Here we show that shRNA-mediated depletion of the mA-forming enzyme METTL3 in human hematopoietic stem/progenitor cells (HSPCs) promotes cell differentiation, coupled with reduced cell proliferation.

Functional screen of MSI2 interactors identifies an essential role for SYNCRIP in myeloid leukemia stem cells.

The identity of the RNA-binding proteins (RBPs) that govern cancer stem cells remains poorly characterized. The MSI2 RBP is a central regulator of translation of cancer stem cell programs. Through proteomic analysis of the MSI2-interacting RBP network and functional shRNA screening, we identified 24 genes required for in vivo leukemia.

The polycomb group protein L3MBTL1 represses a SMAD5-mediated hematopoietic transcriptional program in human pluripotent stem cells.

Epigenetic regulation of key transcriptional programs is a critical mechanism that controls hematopoietic development, and, thus, aberrant expression patterns or mutations in epigenetic regulators occur frequently in hematologic malignancies. We demonstrate that the Polycomb protein L3MBTL1, which is monoallelically deleted in 20q- myeloid malignancies, represses the ability of stem cells to drive hematopoietic-specific transcriptional programs by regulating the expression of SMAD5 and impairing its recruitment to target regulatory regions. Indeed, knockdown of L3MBTL1 promotes the development of hematopoiesis and impairs neural cell fate in human pluripotent stem cells.

PRMT4 blocks myeloid differentiation by assembling a methyl-RUNX1-dependent repressor complex.

Defining the role of epigenetic regulators in hematopoiesis has become critically important, because recurrent mutations or aberrant expression of these genes has been identified in both myeloid and lymphoid hematological malignancies. We found that PRMT4, a type I arginine methyltransferase whose function in normal and malignant hematopoiesis is unknown, is overexpressed in acute myelogenous leukemia patient samples. Overexpression of PRMT4 blocks the myeloid differentiation of human stem/progenitor cells (HSPCs), whereas its knockdown is sufficient to induce myeloid differentiation of HSPCs.

Histone-modifying enzymes: their role in the pathogenesis of acute leukemia and their therapeutic potential.

Histone-modifying enzymes have recently been shown to play a central role in the regulation of both normal and malignant hematopoiesis. Post-translational modifications of histones and non-histone proteins underlies a regulatory complexity affecting numerous processes including transcriptional regulation, RNA processing and DNA damage response. Insights into the functions of these enzymes as well as their role in the epigenetic alterations found in leukemia will guide the development of novel therapeutic approaches.

Affinity-based proteomics reveal cancer-specific networks coordinated by Hsp90.

Most cancers are characterized by multiple molecular alterations, but identification of the key proteins involved in these signaling pathways is currently beyond reach. We show that the inhibitor PU-H71 preferentially targets tumor-enriched Hsp90 complexes and affinity captures Hsp90-dependent oncogenic client proteins. We have used PU-H71 affinity capture to design a proteomic approach that, when combined with bioinformatic pathway analysis, identifies dysregulated signaling networks and key oncoproteins in chronic myeloid leukemia.