Pharmacological inhibition of the MAP2K7 kinase in human disease.

The MAP2K7 signaling pathway activates the c-Jun NH2-terminal protein kinase (JNK) in response to stress signals, such as inflammatory cytokines, osmotic stress, or genomic damage. While there has been interest in inhibiting JNK due to its involvement in inflammatory processes and cancer, there is increasing focus on developing MAP2K7 inhibitors to enhance specificity when MAP2K7 activation is associated with disease progression. Despite some progress, further research is needed to fully comprehend the role of MAP2K7 in cancer and assess the potential use of kinase inhibitors in cancer therapy.

Rational Design of Highly Potent and Selective Covalent MAP2K7 Inhibitors.

The mitogen-activated protein kinase signaling cascade is conserved across eukaryotes, where it plays a critical role in the regulation of activities including proliferation, differentiation, and stress responses. This pathway propagates external stimuli through a series of phosphorylation events, which allows external signals to influence metabolic and transcriptional activities. Within the cascade, MEK, or MAP2K, enzymes occupy a molecular crossroads immediately upstream to significant signal divergence and cross-talk.

SWI/SNF Blockade Disrupts PU.1-Directed Enhancer Programs in Normal Hematopoietic Cells and Acute Myeloid Leukemia.

Unlabelled: In acute myeloid leukemia (AML), SWI/SNF chromatin remodeling complexes sustain leukemic identity by driving high levels of MYC. Previous studies have implicated the hematopoietic transcription factor PU.1 (SPI1) as an important target of SWI/SNF inhibition, but PU.

An ELF4 hypomorphic variant results in NK cell deficiency.

NK cell deficiencies (NKD) are a type of primary immune deficiency in which the major immunologic abnormality affects NK cell number, maturity, or function. Since NK cells contribute to immune defense against virally infected cells, patients with NKD experience higher susceptibility to chronic, recurrent, and fatal viral infections. An individual with recurrent viral infections and mild hypogammaglobulinemia was identified to have an X-linked damaging variant in the transcription factor gene ELF4.

Antileukemic properties of the kinase inhibitor OTSSP167 in T-cell acute lymphoblastic leukemia.

Novel drugs are needed to increase treatment response in children with high-risk T-cell acute lymphoblastic leukemia (T-ALL). Following up on our previous report on the activation of the MAP2K7-JNK pathway in pediatric T-ALL, here we demonstrate that OTSSP167, recently shown to inhibit MAP2K7, has antileukemic capacity in T-ALL. OTSSP167 exhibited dose-dependent cytotoxicity against a panel of T-ALL cell lines with IC50 in the nanomolar range (10-50 nM).

Krüppel-like Factor 4 Supports the Expansion of Leukemia Stem Cells in MLL-AF9-driven Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is an aggressive malignancy of the bone marrow with 5-year overall survival of less than 10% in patients over the age of 65. Limited progress has been made in the patient outcome because of the inability to selectively eradicate the leukemic stem cells (LSC) driving the refractory and relapsed disease. Herein, we investigated the role of the reprogramming factor KLF4 in AML because of its critical role in the self-renewal and stemness of embryonic and cancer stem cells.

CRLF2 overexpression results in reduced B-cell differentiation and upregulated E2F signaling in the Dp16 mouse model of Down syndrome.

Children with Down syndrome (DS) are 10-fold more likely to develop B-cell acute lymphoblastic leukemia (B-ALL), with a higher frequency of rearrangements resulting in overexpression of cytokine receptor-like factor 2 (CRLF2). Here, we investigated the impact of CRLF2 overexpression on B-cell progenitor proliferation, immunophenotype, and gene expression profile in the Dp(16)1Yey (Dp16) mouse model of DS compared with wild-type (WT) mice. CRLF2 overexpression enhanced immature B-lymphoid colony development and increased the proportion of less differentiated pre-pro-B cells, with a greater effect in Dp16 versus WT.

Inhibition of the MAP2K7-JNK pathway with 5Z-7-oxozeaenol induces apoptosis in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive pediatric leukemia with a worse prognosis than most frequent B-cell ALL due to a high incidence of treatment failures and relapse. Our previous work showed that loss of the pioneer factor KLF4 in a NOTCH1-induced T-ALL mouse model accelerated the development of leukemia through expansion of leukemia-initiating cells and activation of the MAP2K7 pathway. Similarly, epigenetic silencing of the gene in children with T-ALL was associated with MAP2K7 activation.

Krüppel-like factor 4 promotes survival and expansion in acute myeloid leukemia cells.

Acute myeloid leukemia (AML) is an aggressive hematological malignancy of the bone marrow that affects mostly elderly adults. Alternative therapies are needed for AML patients because the overall prognosis with current standard of care, high dose chemotherapy and allogeneic transplantation, remains poor due to the emergence of refractory and relapsed disease. Here, we found expression of the transcription factor KLF4 in AML cell lines is not silenced through gene methylation nor via proteasomal degradation.

DYRK2 controls a key regulatory network in chronic myeloid leukemia stem cells.

Chronic myeloid leukemia is a hematological cancer driven by the oncoprotein BCR-ABL1, and lifelong treatment with tyrosine kinase inhibitors extends patient survival to nearly the life expectancy of the general population. Despite advances in the development of more potent tyrosine kinase inhibitors to induce a durable deep molecular response, more than half of patients relapse upon treatment discontinuation. This clinical finding supports the paradigm that leukemia stem cells feed the neoplasm, resist tyrosine kinase inhibition, and reactivate upon drug withdrawal depending on the fitness of the patient's immune surveillance.

Retroviral Transduction of Quiescent Murine Hematopoietic Stem Cells.

Hematopoietic stem cells (HSCs) represent an important target cell population in bone marrow transplantation, cell and gene therapy applications, and the development of leukemia models for research. Because the hematopoietic progeny carries the genetic information of HSCs and replenishes the blood and immune system, corrective gene transfer into HSCs provides an ideal therapeutic approach for many monogenic hematological diseases and a useful tool for studies of HSC function and blood formation in normal and malignant hematopoiesis. However, the efficiency of gene transfer into HSCs has been limited by several features of viral vectors, viral titer, methods of viral transduction, and the property of stem cell quiescence.

Novel tumor-suppressor function of KLF4 in pediatric T-cell acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is the most common hematological malignancy in pediatric patients. Despite advances in the treatment of this disease, many children with T-cell ALL (T-ALL) die from disease relapse due to low responses to standard chemotherapy and the lack of a targeted therapy that selectively eradicates the chemoresistant leukemia-initiating cells (LICs) responsible for disease recurrence. We reported recently that the reprogramming factor Krüppel-like factor 4 (KLF4) has a tumor-suppressive function in children with T-ALL.

Inactivation of KLF4 promotes T-cell acute lymphoblastic leukemia and activates the MAP2K7 pathway.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with a high incidence of relapse in pediatric ALL. Although most T-ALL patients exhibit activating mutations in NOTCH1, the cooperating genetic events required to accelerate the onset of leukemia and worsen disease progression are largely unknown. Here, we show that the gene encoding the transcription factor KLF4 is inactivated by DNA methylation in children with T-ALL.

Role of the reprogramming factor KLF4 in blood formation.

Krüppel-like factor 4 is a zinc finger protein with dual functions that can act as a transcriptional activator and repressor of genes involved in cell proliferation, differentiation, and apoptosis. Although most studies have focused on terminally differentiated epithelial cells, evidence suggests that Krüppel-like factor 4 regulates the development and function of the myeloid and lymphoid blood lineages. The ability of Krüppel-like factor 4 to dedifferentiate from somatic cells into pluripotent stem cells in cooperation with other reprogramming factors suggests its potential function in the preservation of tissue-specific stem cells.

Loss of n-6 fatty acid induced pediatric obesity protects against acute murine colitis.

Dietary influences may affect microbiome composition and host immune responses, thereby modulating propensity toward inflammatory bowel diseases (IBDs): Crohn disease (CD) and ulcerative colitis (UC). Dietary n-6 fatty acids have been associated with UC in prospective studies. However, the critical developmental period when (n-6) consumption may induce UC is not known.

G0S2 modulates homeostatic proliferation of naïve CD8⁺ T cells and inhibits oxidative phosphorylation in mitochondria.

Since its discovery, diverse functions have been attributed to the G0/G1 switch gene 2 (G0S2), from lipid metabolism to control of cell proliferation. Our group showed for the first time that G0S2 promotes quiescence in hematopoietic stem cells by interacting with and retaining nucleolin around the nucleus. Herein, we report the role of G0S2 in the differentiation and function of CD8(+) T cells examined in mice with an embryonic deletion of the G0s2 gene.

From the Table to the Bedside: Can Food-Derived Sulforaphane be used as a Novel Agent to Treat Leukemia?

The extensive use of the same chemotherapeutics over several decades has resulted in a growing incidence of chemoresistant cancer cells and secondary malignancies. Therefore, there is an increasing need for new drugs to treat high-risk cancer patients with a higher selectivity for cancer cells and lower toxicity to normal cells. Sulforaphane is released upon hydrolysis of glucoraphanin, a constituent of cruciferous vegetables, by myrosinases that are present in the plant or intestinal microbes.

Transcription factor ELF4 promotes development and function of memory CD8(+) T cells in Listeria monocytogenes infection.

Most differentiated CD8(+) T cells die off at the end of an infection, revealing two main subsets of memory T cells - central and effector memory - which can be found in lymphoid tissues or circulating through nonlymphoid organs, respectively. The cell intrinsic regulation of the differentiation of CD8(+) T cells to effector and central memory remains poorly studied. Herein, we describe a novel role of the ETS transcription factor ELF4 in the development and function of memory CD8(+) T cells following infection with Listeria monocytogenes.

The transcription factor E74-like factor 4 suppresses differentiation of proliferating CD4+ T cells to the Th17 lineage.

The differentiation of CD4(+) T cells into different Th lineages is driven by cytokine milieu in the priming site and the underlying transcriptional circuitry. Even though many positive regulators have been identified, it is not clear how this process is inhibited at transcriptional level. In this study, we report that the E-twenty six (ETS) transcription factor E74-like factor 4 (ELF4) suppresses the differentiation of Th17 cells both in vitro and in vivo.

G0S2 inhibits the proliferation of K562 cells by interacting with nucleolin in the cytosol.

G0/G1 switch gene 2 (G0S2) is a basic protein with ill-defined function that inhibits the proliferation of hematopoietic stem cells. Herein, we show that treatment of K562 cells with 5-azacytidine (5-Aza) resulted in a 24-fold increase in G0S2 expression and a reduction in cell growth. Conversely, gene demethylation in the presence of G0S2-specific shRNA restored proliferation, further supporting an inhibitory role for G0S2 in cell proliferation.

Differential roles of KLF4 in the development and differentiation of CD8+ T cells.

The transcription factor Krüppel-like factor 4 (KLF4) can activate or repress gene expression in a cell-context dependent manner. We have previously shown that KLF4 inhibits the proliferation of naïve CD8(+) T cells in vitro downstream of the transcription factor ELF4. In this work, we describe a novel role of KLF4 in the differentiation of CD8(+) T cells upon infection.

Genetic control of quiescence in hematopoietic stem cells.

Cellular quiescence is a reversible cell cycle arrest that is poised to re-enter the cell cycle in response to a combination of cell-intrinsic factors and environmental cues. In hematopoietic stem cells, a coordinated balance between quiescence and differentiating proliferation ensures longevity and prevents both genetic damage and stem cell exhaustion. However, little is known about how all these processes are integrated at the molecular level.