Adult Hematopoietic Stem Cells Research Articles

Oncostatin M receptor-dependent signaling assessed by RNA sequencing in mouse hematopoietic stem cells.

Oncostatin M (OSM) is a member of the interleukin-6 (IL-6) family of cytokines and has been found to have anti-inflammatory and pro-inflammatory properties in various cellular and disease contexts. OSM signals through two receptor complexes, one of which includes OSMRβ. Here, we investigated OSM-OSMRβ signaling in adult mouse hematopoietic stem cells (HSCs) using the conditional Osmrfl/fl mouse model B6;129-Osmrtm1.1Nat/J. We crossed Osmrfl/fl mice to interferon-inducible Mx1-Cre, which is robustly induced in adult HSCs. From these mice, we isolated HSCs by flow cytometry, stimulated with recombinant OSM or vehicle for 1 hour, and assessed gene expression changes in control versus Osmr knockout HSCs by RNA-seq. This data may be utilized to investigate OSMRβ -dependent and -independent OSM signaling as well as the transcriptional effects of an IL-6 family cytokine on mouse HSCs to further define its anti-inflammatory versus pro-inflammatory properties.

Hematopoietic stem cell heterogeneity and age-associated platelet bias are evolutionarily conserved.

Hematopoietic stem cells (HSCs) reconstitute multilineage human hematopoiesis after clinical bone marrow (BM) transplantation and are the cells of origin of some hematological malignancies. Although HSCs provide multilineage engraftment, individual murine HSCs are lineage biased and contribute unequally to blood cell lineages. Here, we performed high-throughput single-cell RNA sequencing in mice after xenograft with molecularly barcoded adult human BM HSCs. We demonstrated that human individual BM HSCs are also functionally and transcriptionally lineage biased. Specifically, we identified platelet-biased and multilineage human HSCs. Quantitative comparison of transcriptomes from single HSCs from young and aged BM showed that both the proportion of platelet-biased HSCs and their level of transcriptional platelet priming increase with age. Therefore, platelet-biased HSCs and their increased prevalence and transcriptional platelet priming during aging are conserved features of mammalian evolution.

HES1 is required for mouse fetal hematopoiesis

BackgroundHematopoiesis in mammal is a complex and highly regulated process in which hematopoietic stem cells (HSCs) give rise to all types of differentiated blood cells. Previous studies have shown that hairy and enhancer of split (HES) repressors are essential regulators of adult HSC development downstream of Notch signaling.MethodsIn this study, we investigated the role of HES1, a member of HES family, in fetal hematopoiesis using an embryonic hematopoietic specific Hes1 conditional knockout mouse model by using phenotypic flow cytometry, histopathology analysis, and functional in vitro colony forming unit (CFU) assay and in vivo bone marrow transplant (BMT) assay.ResultsWe found that loss of Hes1 in early embryonic stage leads to smaller embryos and fetal livers, decreases hematopoietic stem progenitor cell (HSPC) pool, results in defective multi-lineage differentiation. Functionally, fetal hematopoietic cells deficient for Hes1 exhibit reduced in vitro progenitor activity and compromised in vivo repopulation capacity in the transplanted recipients. Further analysis shows that fetal hematopoiesis defects in Hes1fl/flFlt3Cre embryos are resulted from decreased proliferation and elevated apoptosis, associated with de-repressed HES1 targets, p27 and PTEN in Hes1-KO fetal HSPCs. Finally, pharmacological inhibition of p27 or PTEN improves fetal HSPCs function both in vitro and in vivo.ConclusionTogether, our findings reveal a previously unappreciated role for HES1 in regulating fetal hematopoiesis, and provide new insight into the differences between fetal and adult HSC maintenance.

Single-cell transcriptomic analysis of hematopoietic progenitor cells from patients with systemic lupus erythematosus reveals interferon-inducible reprogramming in early progenitors.

Immune cells that contribute to the pathogenesis of systemic lupus erythematosus (SLE) derive from adult hematopoietic stem and progenitor cells (HSPCs) within the bone marrow (BM). For this reason, we reasoned that fundamental abnormalities in SLE can be traced to a BM-derived HSPC inflammatory signature. BM samples from four SLE patients, six healthy controls, and two umbilical cord blood (CB) samples were used. CD34+ cells were isolated from BM and CB samples, and single-cell RNA-sequencing was performed. A total of 426 cells and 24,473 genes were used in the analysis. Clustering analysis resulted in seven distinct clusters of cell types. Mutually exclusive markers, which were characteristic of each cell type, were identified. We identified three HSPC subpopulations, one of which consisted of proliferating cells (MKI67 expressing cells), one T-like, one B-like, and two myeloid-like progenitor subpopulations. Differential expression analysis revealed i) cell cycle-associated signatures, in healthy BM of HSPC clusters 3 and 4 when compared with CB, and ii) interferon (IFN) signatures in SLE BM of HSPC clusters 3 and 4 and myeloid-like progenitor cluster 5 when compared with healthy controls. The IFN signature in SLE appeared to be deregulated following TF regulatory network analysis and differential alternative splicing analysis between SLE and healthy controls in HSPC subpopulations. This study revealed both quantitative-as evidenced by decreased numbers of non-proliferating early progenitors-and qualitative differences-characterized by an IFN signature in SLE, which is known to drive loss of function and depletion of HSPCs. Chronic IFN exposure affects early hematopoietic progenitors in SLE, which may account for the immune aberrancies and the cytopenias in SLE.

Kinase-inactivated CDK6 preserves the long-term functionality of adult hematopoietic stem cells

AbstractHematopoietic stem cells (HSCs) are characterized by the ability to self-renew and to replenish the hematopoietic system. The cell-cycle kinase cyclin-dependent kinase 6 (CDK6) regulates transcription, whereby it has both kinase-dependent and kinase-independent functions. Herein, we describe the complex role of CDK6, balancing quiescence, proliferation, self-renewal, and differentiation in activated HSCs. Mouse HSCs expressing kinase-inactivated CDK6 show enhanced long-term repopulation and homing, whereas HSCs lacking CDK6 have impaired functionality. The transcriptomes of basal and serially transplanted HSCs expressing kinase-inactivated CDK6 exhibit an expression pattern dominated by HSC quiescence and self-renewal, supporting a concept, in which myc-associated zinc finger protein (MAZ) and nuclear transcription factor Y subunit alpha (NFY-A) are critical CDK6 interactors. Pharmacologic kinase inhibition with a clinically used CDK4/6 inhibitor in murine and human HSCs validated our findings and resulted in increased repopulation capability and enhanced stemness. Our findings highlight a kinase-independent role of CDK6 in long-term HSC functionality. CDK6 kinase inhibition represents a possible strategy to improve HSC fitness.

Age-specific induction of mutant p53 drives clonal hematopoiesis and acute myeloid leukemia in adult mice

The investigation of the mechanisms behind p53 mutations in acute myeloid leukemia (AML) has been limited by the lack of suitable mouse models, which historically have resulted in lymphoma rather than leukemia. This study introduces two new AML mouse models. One model induces mutant p53 and Mdm2 haploinsufficiency in early development, showing the role of Mdm2 in myeloid-biased hematopoiesis and AML predisposition, independent of p53. The second model mimics clonal hematopoiesis by inducing mutant p53 in adult hematopoietic stem cells, demonstrating that the timing of p53 mutation determines AML vs. lymphoma development. In this context, age-related changes in hematopoietic stem cells (HSCs) collaborate with mutant p53 to predispose toward myeloid transformation rather than lymphoma development. Our study unveils new insights into the cooperative impact of HSC age, Trp53 mutations, and Mdm2 haploinsufficiency on clonal hematopoiesis and the development of myeloid malignancies.

The ATF4-RPS19BP1 axis modulates ribosome biogenesis to promote erythropoiesis

AbstractHematopoietic differentiation is controlled by intrinsic regulators and the extrinsic hematopoietic niche. Activating transcription factor 4 (ATF4) plays a crucial role in the function of fetal and adult hematopoietic stem cell maintenance. However, the precise function of ATF4 in the bone marrow (BM) niche and the mechanism by which ATF4 regulates adult hematopoiesis remain largely unknown. Here, we used 4 cell-type-specific mouse Cre lines to achieve conditional knockout of Atf4 in Cdh5+ endothelial cells, Prx1+ BM stromal cells, Osx+ osteoprogenitor cells, and Mx1+ hematopoietic cells and uncovered the role of Atf4 in niche cells and hematopoiesis. Intriguingly, depletion of Atf4 in niche cells did not affect hematopoiesis; however, Atf4-deficient hematopoietic cells exhibited erythroid differentiation defects, leading to hypoplastic anemia. Mechanistically, ATF4 mediated direct regulation of Rps19bp1 transcription, which is, in turn, involved in 40 S ribosomal subunit assembly to coordinate ribosome biogenesis and promote erythropoiesis. Finally, we demonstrate that under conditions of 5-fluorouracil–induced stress, Atf4 depletion impedes the recovery of hematopoietic lineages, which requires efficient ribosome biogenesis. Taken together, our findings highlight the indispensable role of the ATF4-RPS19BP1 axis in the regulation of erythropoiesis.

A retrospective study of intravenous pentamidine for Pneumocystis jirovecii pneumonia prophylaxis in adult patients with hematologic malignancies—its utility during respiratory virus pandemics

ObjectivesIn hematology, prophylaxis for Pneumocystis jirovecii pneumonia (PCP) is recommended for patients undergoing hematopoietic stem cell transplantation and in selected categories of intensive chemotherapy for hematologic malignancies. Trimethoprim-sulfamethoxazole (TMP-SMX) is the recommended first-line agent; however, its use is not straightforward. Inhaled pentamidine is the recommended second-line agent; however, aerosolized medications were discouraged during respiratory virus outbreaks, especially during the COVID-19 pandemic, in view of potential contamination risks. Intravenous (IV) pentamidine is a potential alternative agent. We evaluated the effectiveness and tolerability of IV pentamidine use for PCP prophylaxis in adult allogeneic hematopoietic stem cell transplantation recipients and patients with hematologic malignancies during COVID-19. ResultsA total of 202 unique patients who received 239 courses of IV pentamidine, with a median of three doses received (1-29). The largest group of the patients (49.5%) who received IV pentamidine were undergoing or had received a hematopoietic stem cell transplant. The most common reason for not using TMP-SMX prophylaxis was cytopenia (34.7%). We have no patients who had breakthrough PCP infection while on IV pentamidine. None of the patients developed an infusion reaction or experienced adverse effects from IV pentamidine. ConclusionsPentamidine administered IV monthly is safe and effective.

IMPROVE-BMT: A Pilot Randomized Controlled Trial of Prehabilitation Exercise for Adult Hematopoietic Stem Cell Transplant Recipients.

Background: There is limited evidence on the effects of aerobic and resistance training exercise interventions to improve physical function and patient-reported outcomes prior to autologous and allogeneic hematopoietic stem cell transplant (HSCT). IMPROVE-BMT was a single-site, pilot randomized controlled trial investigating the feasibility, acceptability, and safety of a pragmatic resistance training exercise program prior to HSCT compared to usual HSCT care. Secondary aims included differences in physical function between the exercise group (EX) and usual care control group (UC). Methods: Outcome measurements were assessed: prior to HSCT, on/around day of HSCT admission, +30 days post-HSCT, and +100 days post-HSCT. The exercise intervention was a home-based exercise program that incorporated resistance-band and bodyweight exercises. Results: Acceptability among participants was 83%; exercise adherence averaged at 92%; and there were zero exercise-related adverse or serious adverse events. The average pre-transplant exercise phase was 6.28 weeks (2.71-18.29 weeks). EX (n = 36) demonstrated larger increases in the six-minute walk test distance, short physical performance battery scores, and 30-s chair stands compared to UC (n = 38) and demonstrated significant within-group improvements for the six-minute walk test, the short physical performance battery, the 30-s chair stands, and the timed up-and-go test. Conclusions: IMPROVE-BMT demonstrates that pragmatic exercise is highly feasible for HSCT recipients and can potentially lead to enhanced recovery that may not be achievable in non-exercisers.

Qualityof life in the digital age: young adult hematopoietic stem cell transplantation patients and healthcare providers' views of telehealth.

The COVID-19 pandemic shifted the healthcare field from in-person clinic visits to virtual-based telehealth appointments. This study explored young adult (YA) hematopoietic stem cell transplantation (HSCT) patient and physician communication preferences and quality of life. One researcher conducted semi-structured interviews with n = 10 YA HSCT patients and n = 10 healthcare providers (HPs). HPs included physicians (n = 5) and advanced practice provider (APP) (nurse practitioners and physician assistants) (n = 5). Interviews lasted approximately 10-15min, were held over Zoom®, and were audio-recorded. Interviews were professionally transcribed verbatim, and two independent researchers conducted a thematic analysis using Dedoose®. Common themes included the following: (1) convenience, (2) improved communication, (3) technology issues, and (4) quality of life for patients and physicians. In general, most patients (n = 7; 70%) preferred in-person visits over telehealth for initial appointments, stating they chose the "social connection" and "engagement" associated with in-person visits. For "check-ins" and follow-up appointments (n = 5; 50%), patients preferred hybrid appointments. Physicians (n = 4; 80%) preferred telehealth stating it was "convenient," "timesaving," and improved "compliance." In contrast, all APP staff (n = 5; 100%) preferred in-person visits, stating in-person improved "relationships" with patients and was more "convenient" than using electronic devices for telehealth. Providers differed in preference. APP personnel preferred in-person visits and HSCT physicians preferred telehealth appointments. YA HSCT patients preferred in-person for initial appointments and hybrid clinic visits for follow-up appointments.

Presentation, management, and outcomes of norovirus in adult and pediatric solid organ and hematopoietic stem cell transplant recipients: A multicenter, retrospective study.

Norovirus (NoV) can cause chronic relapsing and remitting diarrhea in immunocompromised patients. Few multicenter studies have described the clinical course, outcomes, and complications of chronic NoV in transplant recipients. A multicenter retrospective study of adult and pediatric SOT and HSCT recipients diagnosed with NoV between November 1, 2017, and February 28, 2021. Data were obtained from electronic medical records (EMR) and entered into a central REDCap database. Descriptive statistics were calculated. A total of 280 NoV+ patients were identified across eight sites. The majority were adults (74.1%) and SOT recipients (91.4%). Initial diagnosis of NoV occurred a median of 36 months post-Tx (IQR [15.0, 90.0]). Most NoV cases had >3 diarrheal episodes daily (66.0%), nausea and vomiting (60.1%). Duration of diarrhea varied greatly (median = 10 days, mean = 85.9 days, range (1, 2100)). 71.3% were hospitalized. Adjustment of immunosuppression, including reduction and discontinuation of mToR inhibitor, CNI, and/or MMF, was the most common management intervention for NoV. Other therapies resulted only in temporary improvement. Four patients died within 30 days and three others died by 180 days postdiagnosis. Clinically significant renal dysfunction was observed in 12.5% by 30 days and 21.4% by 180 days post-NoV diagnosis. In HSCT and SOT patients, NoV frequently resulted in severe symptoms, prolonged diarrhea (30% persistent with diarrhea for >30 days), and clinically significant renal dysfunction (up to 21% of patients). Utilized therapies did not reliably result in the resolution of infection demonstrating the need for more effective treatment.

Improving hematopoietic differentiation from human induced pluripotent stem cells by the modulation of Hippo signaling with a diarylheptanoid derivative

BackgroundThe diarylheptanoid ASPP 049 has improved the quality of adult hematopoietic stem cell (HSC) expansion ex vivo through long-term reconstitution in animal models. However, its effect on hematopoietic regeneration from human induced pluripotent stem cells (hiPSCs) is unknown.MethodWe utilized a defined cocktail of cytokines without serum or feeder followed by the supplementation of ASPP 049 to produce hematopoietic stem/progenitor cells (HSPCs). Flow cytometry and trypan blue exclusion analysis were used to identify nonadherent and adherent cells. Nonadherent cells were harvested to investigate the effect of ASPP 049 on multipotency using LTC-IC and CFU assays. Subsequently, the mechanism of action was explored through transcriptomic profiles, which were validated by qRT-PCR, immunoblotting, and immunofluorescence analysis.ResultThe supplementation of ASPP 049 increased the number of phenotypically defined primitive HSPCs (CD34+CD45+CD90+) two-fold relative to seeded hiPSC colonies, indicating enhanced HSC derivation from hiPSCs. Under ASPP 049-supplemented conditions, we observed elevated HSPC niches, including CD144+CD73− hemogenic- and CD144+CD73+ vascular-endothelial progenitors, during HSC differentiation. Moreover, harvested ASPP 049-treated cells exhibited improved self-renewal and a significantly larger proportion of different blood cell colonies with unbiased lineages, indicating enhanced HSC stemness properties. Transcriptomics and KEGG analysis of sorted CD34+CD45+ cells-related mRNA profiles revealed that the Hippo signaling pathway is the most significant in responding to WWTR1/TAZ, which correlates with the validation of the protein expression. Interestingly, ASPP 049-supplemented HSPCs upregulated 11 genes similarly to umbilical cord blood-derived HSPCs.ConclusionThese findings suggest that ASPP 049 can improve HSC-generating protocols with proliferative potentials, self-renewal ability, unbiased differentiation, and a definable mechanism of action for the clinical perspective of hematopoietic regenerative medicine.Graphical abstract

Differentiation of regulatory myeloid and T-cells from adult human hematopoietic stem cells after allogeneic stimulation.

Donor hematopoietic stem cell (DHSC) infusions are increasingly being studied in transplant patients for tolerance induction. To analyze the fate of infused DHSCs in patients, we developed an in vitro culture system utilizing CD34+DHSCs stimulated with irradiated allogeneic cells in cytokine supplemented medium long-term. Flow cytometric analyses revealed loss of the CD34 marker and an increase in CD33+ myeloid and CD3+ T-cell proportion by 10.4% and 72.7%, respectively, after 21 days in culture. T-cells primarily expressed TcR-αβ and were of both CD4+ and CD8+ subsets. Approximately 80% of CD3+ T cells lacked expression of the co-stimulatory receptor CD28. The CD4+ compartment was predominated by CD4+CD25+CD127-FOXP3+ Tregs (>50% CD4+CD127- compartment) with <1% of all leukocytes exhibiting a CD4+CD127+ phenotype. Molecular analyses for T-cell receptor excision circles showed recent and increased numbers of TcR rearrangements in generated T cells over time suggesting de novo differentiation from DHSCs. CD33+ myeloid cells mostly expressed HLA-DR, but lacked expression of co-stimulatory receptors CD80 and CD83. When studied as modulators in primary mixed lymphocyte reactions where the cells used to stimulate the DHSC were used as responders, the DHSC-lines and their purified CD8+, CD4+, CD33+ and linage negative subsets inhibited the responses in a dose-dependent and non-specific fashion. The CD8+ cell-mediated inhibition was due to direct lysis of responder cells. Extrapolation of these results into the clinical situation would suggest that DHSC infusions into transplant recipients may generate multiple subsets of donor "chimeric" cells and promote recipient Treg development that could regulate the anti-donor immune response in the periphery. These studies have also indicated that T cell maturation can occur in vitro in response to allogeneic stimulation without the pre-requisite of a thymic-like environment or NOTCH signaling stimulatory cell line.

Engraftment of adult hematopoietic stem and progenitor cells in a novel model of humanized mice

Pre-clinical use of humanized mice transplanted with CD34+ hematopoietic stem and progenitor cells (HSPCs) is limited by insufficient engraftment with adult non-mobilized HSPCs. Here, we developed a novel immunodeficient mice based on NOD-SCID-Il2γc-/- (NSG) mice to support long-term engraftment with human adult HSPCs. As both Flt3L and IL-6 are critical for many aspects of hematopoiesis, we knock-out mouse Flt3 and knock-in human IL6 gene. The resulting mice showed an increase in the availability of mouse Flt3L to human cells and a dose-dependent production of human IL-6 upon activation. Upon transplantation with low number of human HSPCs from adult bone marrow, these humanized mice demonstrated a significantly higher engraftment with multilineage differentiation of human lymphoid and myeloid cells, and tissue colonization at one year after adult HSPC transplant. Thus, these mice enable studies of human hematopoiesis and tissue colonization over time and may facilitate building autologous models for immuno-oncology studies.

Invasive Fungal Infections Are Rare in Pediatric and Young Adult Autologous Hematopoietic Stem Cell Transplant Patients

Invasive Fungal Infections Are Rare in Pediatric and Young Adult Autologous Hematopoietic Stem Cell Transplant Patients

Letermovir for Cytomegalovirus infection in pediatric patients undergoing allogenic hematopoietic stem cell transplantation: a real-life study by the Infectious Diseases Working Group of Italian Association of Pediatric Hematology-Oncology (AIEOP).

Letermovir prophylaxis revolutionized the approach to Cytomegalovirus infection in adult hematopoietic stem cell transplant (HCT), while data in pediatric setting are still lacking. We retrospectively analyzed 87 HCT children transplanted in 11 AIEOP centers receiving letermovir as off-label indication between January 2020 and November 2022. Letermovir was used as primary, secondary prophylaxis or CMV treatment in 39, 26 and 22 cases, respectively; no discontinuation due to toxicity was reported. Median duration was 100 days (14-256) for primary and 96 days (8-271) for secondary prophylaxis, respectively. None of the patients experienced CMV-clinically significant reactivation during Letermovir primary prophylaxis; one patient developed breakthrough infection during secondary prophylaxis, and 10 and 1 patient experienced asymptomatic CMV-reactivation and CMV-primary infection after drug discontinuation, respectively. Median duration of letermovir in CMV treatment was 40 days (7-134), with 4/22 patients suffering CMV-pneumonia, with an overall response rate of 86.4%. With a median follow-up of 10.7 months (8.2-11.8), estimated 1-year overall survival was 86%; no CMV-related deaths were reported in prophylaxis groups. This is the largest report on Letermovir use in pediatric HCT; real-life data confirm an excellent toxicity profile, with high efficacy as CMV prophylaxis; results in CMV-infection treatment should be investigated in larger, prospective trials.

Novel ABCD1 variant causes phenotype of adrenomyeloneuropathy with cerebral involvement in Ukrainian siblings: first adult hematopoietic stem cell transplantation for ALD in Ukraine: a case report

BackgroundThis article presents a case study of two white male siblings of 24 and 31 years of age of self-reported Ukrainian ethnicity diagnosed with adrenomyeloneuropathy (AMN) associated with a novel splice site mutation in the ABCD1 gene. AMN represents a form of X-linked adrenoleukodystrophy (X-ALD) characterized by demyelination of the spinal cord and peripheral nerves. The case also presents the first adult haematopoietic stem cell transplant (HSCT) for adrenomyeloneuropathy in Ukraine. The rarity of this mutation and its cerebral involvement and the treatment make this case noteworthy and underscore the significance of reporting it to contribute to the existing medical knowledge.Case presentationThe patients of 24 and 31 years initially exhibited progressive gait disturbance, lower extremity pain, and urinary incontinence, with the older sibling experiencing more advanced symptoms of speech, hearing, and vision disturbances. A comprehensive genetic analysis identified an unreported splice site mutation in exon 3 of the ABCD1 gene, leading to the manifestation of AMN. The inheritance pattern was consistent with X-linked recessive transmission. The article also outlines the clinical features, magnetic resonance imaging (MRI), and nerve conduction study (NCS) findings. Moreover, it discusses the genetic profile of the affected individuals and female carriers within the family. The younger sibling underwent HSCT, which was complicated by mediastinal lymph node and lung tuberculosis, adding to the complexity of managing adult ALD patients.ConclusionsThis report emphasizes the importance of genetic testing in diagnosing and comprehending the underlying mechanisms of rare genetic disorders, such as AMN with cerebral involvement. The identification of a novel splice site mutation expands our understanding of the genetic landscape of this condition. Additionally, the challenges and complications encountered during the hematopoietic stem cell transplant procedure underscore the need for cautious consideration and personalized approaches in adult ALD patients.

Clinical Relevance of Therapeutic Drug Monitoring of Busulfan-Based Regimens in Adult Hematopoietic Stem Cell Transplant Patients

Clinical Relevance of Therapeutic Drug Monitoring of Busulfan-Based Regimens in Adult Hematopoietic Stem Cell Transplant Patients

The Diverse Roles of ETV6 Alterations in B-Lymphoblastic Leukemia and Other Hematopoietic Cancers.

Genetic alterations of the repressive ETS family transcription factor gene ETV6 are recurrent in several categories of hematopoietic malignancy, including subsets of B-cell and T-cell acute lymphoblastic leukemias (B-ALL and T-ALL), myeloid neoplasms, and mature B-cell lymphomas. ETV6 is essential for adult hematopoietic stem cells (HSCs), contributes to specific functions of some mature immune cells, and plays a key role in thrombopoiesis as demonstrated by familial ETV6 mutations associated with thrombocytopenia and predisposition to hematopoietic cancers, particularly B-ALL. ETV6 appears to have a tumor suppressor role in several hematopoietic lineages, as demonstrated by recurrent somatic loss-of-function (LoF) and putative dominant-negative alterations in leukemias and lymphomas. ETV6 rearrangements contribute to recurrent fusion oncogenes such as the B-ALL-associated transcription factor (TF) fusions ETV6::RUNX1 and PAX5::ETV6, rare drivers such as ETV6::NCOA6, and a spectrum of tyrosine kinase gene fusions encoding hyperactive signaling proteins that self-associate via the ETV6 N-terminal pointed domain. Another subset of recurrent rearrangements involving the ETV6 gene locus appear to function primarily to drive overexpression of the partner gene. This review surveys what is known about the biochemical and genome regulatory properties of ETV6 as well as our current understanding of how alterations in these functions contribute to hematopoietic and nonhematopoietic cancers.

Post-transcriptional (re)programming of B lymphocyte development: From bench to bedside?

Hematopoiesis, a process which generates blood and immune cells, changes significantly during mammalian development. Definitive hematopoiesis is marked by the emergence of long-term hematopoietic stem cells (HSCs). Here, we will focus on the post-transcriptional differences between fetal liver (FL) and adult bone marrow (ABM) HSCs. It remains unclear how or why exactly FL HSCs transition to ABM HSCs, but we aim to leverage their differences to revive an old idea: in utero HSC transplantation. Unexpectedly, the expression of certain RNA-binding proteins (RBPs) play an important role in HSC specification, and can be employed to convert or reprogram adult HSCs back to a fetal-like state. Among other features, FL HSCs have a broad differentiation capacity that includes the ability to regenerate both conventional B and T cells, as well as innate-like or unconventional lymphocytes such as B-1a and marginal zone B (MzB) cells. This chapter will focus on RNA binding proteins, namely LIN28B and IGF2BP3, that are expressed during fetal life and how they promote B-1a cell development. Furthermore, this chapter considers a potential clinical application of synthetic co-expression of LIN28B and IGF2BP3 in HSCs.