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RNA interference-mediated inhibition of JAK/STAT expression reduces growth and survival of human AML CD34 1 cells. (A) AML CD34 1 cells (AML 404, 571, and 636) were exposed to siRNA to JAK1, JAK2, STAT3, and STAT5a/b and negative control siRNA by nucleofection. Knockdown of target proteins was evaluated by western blotting. (B-D) Nucleofected cells were cultured for 72 hours and (B) enumerated (n 5 3) and assessed for (C) apoptosis (n 5 4) and (D) CFC growth (n 5 3). (E) AML CD34 1 cells (AML 545, 614, 704, and 755) were exposed to a second set of siRNA to JAK1, JAK2, STAT3, and STAT5a/b and control siRNA (negative control), and (F) the effect of JAK1/2 knockdown on pSTAT3/5 expression was evaluated by western blotting. Nucleofected cells were cultured for 72 hours and (G) enumerated (n 5 3) and assessed for (H) apoptosis (n 5 4) and (I) CFC growth (n 5 3). (J-L) CB CD34 1 cells (n 5 3) were exposed to siRNA to JAK1, JAK2, STAT3, and STAT5a/b and control siRNA (negative control) and assessed for (J) knockdown of target proteins by western blotting and for (K) apoptosis and (L) CFC growth. Results represent the mean 6 SEM. Significance values: *P , .05, **P , .01.
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Acute myeloid leukemia (AML) is sustained by small populations of leukemia stem cells (LSCs) that can resist available treatments and represent important barriers to cure. Although previous studies have shown increased signal transducer and activator of transcription (STAT)3 and STAT5 phosphorylation in AML leukemic blasts, the role of Janus kinase...
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... further assessed the role of the JAK signaling in AML CD34 1 cells by siRNA-mediated knockdown of JAK1, JAK2, STAT3, and STAT5a and STAT5b (in combination). We verified knockdown of targeted proteins in siRNA-treated cells ( Figure 3A). JAK2, STAT3, and STAT5a/b knockdown significantly decreased cell numbers ( Figure 3B), increased apoptosis ( Figure 3C), and inhibited CFC ( Figure 3D) compared with control siRNA, with less inhibition seen with JAK1 knockdown. ...
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... verified knockdown of targeted proteins in siRNA-treated cells ( Figure 3A). JAK2, STAT3, and STAT5a/b knockdown significantly decreased cell numbers ( Figure 3B), increased apoptosis ( Figure 3C), and inhibited CFC ( Figure 3D) compared with control siRNA, with less inhibition seen with JAK1 knockdown. We used a second set of siRNAs targeting different sequences in JAK1, JAK2, STAT3, and STAT5 to validate these results. ...
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... verified knockdown of targeted proteins in siRNA-treated cells ( Figure 3A). JAK2, STAT3, and STAT5a/b knockdown significantly decreased cell numbers ( Figure 3B), increased apoptosis ( Figure 3C), and inhibited CFC ( Figure 3D) compared with control siRNA, with less inhibition seen with JAK1 knockdown. We used a second set of siRNAs targeting different sequences in JAK1, JAK2, STAT3, and STAT5 to validate these results. ...
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... verified knockdown of targeted proteins in siRNA-treated cells ( Figure 3A). JAK2, STAT3, and STAT5a/b knockdown significantly decreased cell numbers ( Figure 3B), increased apoptosis ( Figure 3C), and inhibited CFC ( Figure 3D) compared with control siRNA, with less inhibition seen with JAK1 knockdown. We used a second set of siRNAs targeting different sequences in JAK1, JAK2, STAT3, and STAT5 to validate these results. ...
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... used a second set of siRNAs targeting different sequences in JAK1, JAK2, STAT3, and STAT5 to validate these results. We confirmed inhibition of target gene expression in AML cells ( Figure 3E). Inhibition of JAK1 resulted in reduced pSTAT3 but not STAT5 levels, whereas inhibition of JAK2 resulted in inhibition of both pSTAT3 and pSTAT5 levels ( Figure 3F). ...
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... confirmed inhibition of target gene expression in AML cells ( Figure 3E). Inhibition of JAK1 resulted in reduced pSTAT3 but not STAT5 levels, whereas inhibition of JAK2 resulted in inhibition of both pSTAT3 and pSTAT5 levels ( Figure 3F). We observed significant reduction of cell numbers ( Figure 3G), survival ( Figure 3H), and CFC ( Figure 3I) following JAK2, STAT3, and STAT5 knockdown. ...
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... of JAK1 resulted in reduced pSTAT3 but not STAT5 levels, whereas inhibition of JAK2 resulted in inhibition of both pSTAT3 and pSTAT5 levels ( Figure 3F). We observed significant reduction of cell numbers ( Figure 3G), survival ( Figure 3H), and CFC ( Figure 3I) following JAK2, STAT3, and STAT5 knockdown. In contrast, the second JAK1 siRNA did not inhibit AML CD34 1 cell survival or growth. ...
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... of JAK1 resulted in reduced pSTAT3 but not STAT5 levels, whereas inhibition of JAK2 resulted in inhibition of both pSTAT3 and pSTAT5 levels ( Figure 3F). We observed significant reduction of cell numbers ( Figure 3G), survival ( Figure 3H), and CFC ( Figure 3I) following JAK2, STAT3, and STAT5 knockdown. In contrast, the second JAK1 siRNA did not inhibit AML CD34 1 cell survival or growth. ...
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... of JAK1 resulted in reduced pSTAT3 but not STAT5 levels, whereas inhibition of JAK2 resulted in inhibition of both pSTAT3 and pSTAT5 levels ( Figure 3F). We observed significant reduction of cell numbers ( Figure 3G), survival ( Figure 3H), and CFC ( Figure 3I) following JAK2, STAT3, and STAT5 knockdown. In contrast, the second JAK1 siRNA did not inhibit AML CD34 1 cell survival or growth. ...
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... contrast, the second JAK1 siRNA did not inhibit AML CD34 1 cell survival or growth. JAK2 inhibition by lentivirus-mediated JAK2 shRNA expression also resulted in marked inhibition of pSTAT3 and pSTAT5 ex- pression in AML KG1a cells (supplemental Figure 3A), with signi- ficant inhibition of cell growth (supplemental Figure 3B) and apoptosis induction (supplemental Figure 3C). JAK1, JAK2, STAT3, and STAT5 knockdown ( Figure 3J) did not significantly induce apoptosis in CB CD34 1 cells ( Figure 3K) or inhibit CFC growth, other than modest but significant inhibition with STAT3 knockdown ( Figure 3L ...
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... contrast, the second JAK1 siRNA did not inhibit AML CD34 1 cell survival or growth. JAK2 inhibition by lentivirus-mediated JAK2 shRNA expression also resulted in marked inhibition of pSTAT3 and pSTAT5 ex- pression in AML KG1a cells (supplemental Figure 3A), with signi- ficant inhibition of cell growth (supplemental Figure 3B) and apoptosis induction (supplemental Figure 3C). JAK1, JAK2, STAT3, and STAT5 knockdown ( Figure 3J) did not significantly induce apoptosis in CB CD34 1 cells ( Figure 3K) or inhibit CFC growth, other than modest but significant inhibition with STAT3 knockdown ( Figure 3L ...
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... contrast, the second JAK1 siRNA did not inhibit AML CD34 1 cell survival or growth. JAK2 inhibition by lentivirus-mediated JAK2 shRNA expression also resulted in marked inhibition of pSTAT3 and pSTAT5 ex- pression in AML KG1a cells (supplemental Figure 3A), with signi- ficant inhibition of cell growth (supplemental Figure 3B) and apoptosis induction (supplemental Figure 3C). JAK1, JAK2, STAT3, and STAT5 knockdown ( Figure 3J) did not significantly induce apoptosis in CB CD34 1 cells ( Figure 3K) or inhibit CFC growth, other than modest but significant inhibition with STAT3 knockdown ( Figure 3L ...
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... inhibition by lentivirus-mediated JAK2 shRNA expression also resulted in marked inhibition of pSTAT3 and pSTAT5 ex- pression in AML KG1a cells (supplemental Figure 3A), with signi- ficant inhibition of cell growth (supplemental Figure 3B) and apoptosis induction (supplemental Figure 3C). JAK1, JAK2, STAT3, and STAT5 knockdown ( Figure 3J) did not significantly induce apoptosis in CB CD34 1 cells ( Figure 3K) or inhibit CFC growth, other than modest but significant inhibition with STAT3 knockdown ( Figure 3L ...
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... inhibition by lentivirus-mediated JAK2 shRNA expression also resulted in marked inhibition of pSTAT3 and pSTAT5 ex- pression in AML KG1a cells (supplemental Figure 3A), with signi- ficant inhibition of cell growth (supplemental Figure 3B) and apoptosis induction (supplemental Figure 3C). JAK1, JAK2, STAT3, and STAT5 knockdown ( Figure 3J) did not significantly induce apoptosis in CB CD34 1 cells ( Figure 3K) or inhibit CFC growth, other than modest but significant inhibition with STAT3 knockdown ( Figure 3L ...
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... inhibition by lentivirus-mediated JAK2 shRNA expression also resulted in marked inhibition of pSTAT3 and pSTAT5 ex- pression in AML KG1a cells (supplemental Figure 3A), with signi- ficant inhibition of cell growth (supplemental Figure 3B) and apoptosis induction (supplemental Figure 3C). JAK1, JAK2, STAT3, and STAT5 knockdown ( Figure 3J) did not significantly induce apoptosis in CB CD34 1 cells ( Figure 3K) or inhibit CFC growth, other than modest but significant inhibition with STAT3 knockdown ( Figure 3L ...
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... The JAK/STAT pathway has an essential role in AML-LSCs by targeting various growth factor receptors. 185 Bone morphogenetic protein receptor type-1B (BMPR1B) as a stem cell modulator also affect persisting and dormant LSCs invisible in their BM niche. 186 Interleukin pathway Tregs are one of the leading causes of immunosuppression in the bone marrow niche. ...
Leukemia is a malignancy in the blood that develops from the lymphatic system and bone marrow. Although various treatment options have been used for different types of leukemia, understanding the molecular pathways involved in the development and progression of leukemia is necessary. Recent studies showed that leukemia stem cells (LSCs) play essential roles in the pathogenesis of leukemia by targeting several signaling pathways, including Notch, Wnt, Hedgehog, and STAT3. LSCs are highly proliferative cells that stimulate tumor initiation, migration, EMT, and drug resistance. This review summarizes cellular pathways that stimulate and prevent LSCs' self-renewal, metastasis, and tumorigenesis.
... progenitor/stem cells of high-risk adult AML 15 . Consistent with a role for IL-6 signaling in treatment resistance, inhibition of JAK/STAT signaling sensitizes AML blasts to treatment with other drugs 16 , as well as reducing the proliferation rate of adult AML cells 17 . ...
High levels of the inflammatory cytokine IL-6 in the bone marrow are associated with poor outcomes in pediatric acute myeloid leukemia (pAML), but its etiology remains unknown. Using RNA-seq data from pre-treatment bone marrows of 1489 children with pAML, we show that > 20% of patients have concurrent IL-6, IL-1, IFNα/β, and TNFα signaling activity and poorer outcomes. Targeted sequencing of pre-treatment bone marrow samples from affected patients (n = 181) revealed 5 highly recurrent patterns of somatic mutation. Using differential expression analyses of the most common genomic subtypes (~60% of total), we identify high expression of multiple potential drivers of inflammation-related treatment resistance. Regardless of genomic subtype, we show that JAK1/2 inhibition reduces receptor-mediated inflammatory signaling by leukemic cells in-vitro. The large number of high-risk pAML genomic subtypes presents an obstacle to the development of mutation-specific therapies. Our findings suggest that therapies targeting inflammatory signaling may be effective across multiple genomic subtypes of pAML.
... As reported previously, growth factors, such as stem cell factor (SCF), interleukin 3 (IL-3), and granulocyte-colony stimulating factor (G-CSF) play an important role in the maintenance of LSC stemness and survival [4]. Accordingly, phenotypically high expression of growth factor receptors, such as IL-3 receptor (CD123), c-kit, and FMS-related tyrosine kinase 3 (FLT3), or genetic mutations in these receptors or their downstream pathways, such as neuroblastoma RAS viral (v-ras) oncogene homolog (N-RAS), were observed in the LSCs of AML, which incurred the overactivation of their downstream tyrosine kinases [11][12][13]. Such overactivation could be engaged in the proliferation, apoptosis, and immune evasion through multiple signaling pathways, especially JAK/STAT [11,14]. ...
... Accordingly, phenotypically high expression of growth factor receptors, such as IL-3 receptor (CD123), c-kit, and FMS-related tyrosine kinase 3 (FLT3), or genetic mutations in these receptors or their downstream pathways, such as neuroblastoma RAS viral (v-ras) oncogene homolog (N-RAS), were observed in the LSCs of AML, which incurred the overactivation of their downstream tyrosine kinases [11][12][13]. Such overactivation could be engaged in the proliferation, apoptosis, and immune evasion through multiple signaling pathways, especially JAK/STAT [11,14]. STAT3/5 is the downstream of JAK2 signaling, which regulates the chemo-sensitivity through influencing the balance between pro-and anti-apoptotic proteins, such as Bcl-2 and Bcl-xL, and affecting the expression of immune checkpoint ligands, such as PD-L1 [15][16][17]. ...
... STAT3/5 is the downstream of JAK2 signaling, which regulates the chemo-sensitivity through influencing the balance between pro-and anti-apoptotic proteins, such as Bcl-2 and Bcl-xL, and affecting the expression of immune checkpoint ligands, such as PD-L1 [15][16][17]. Notably, STAT3/5 activation has been dependent on the growth factor signaling in LSCs [11], implying that targeting growth factor receptors and their downstream signaling might be effective for eliminating LSCs. ...
Leukemia stem cells (LSCs) constitute the critical barrier to the cure of acute myeloid leukemia (AML) due to their chemoresistance and immune evasion property. Herein, the role of anlotinib, a multiple tyrosine kinase inhibitor, in killing LSCs and regulating chemoresistance and immune evasion was explored. Anlotinib treatment induced apoptosis of LSC-like cells as well as primary AML LSCs, while sparing the normal mononuclear cells in vitro. Moreover, anlotinib could impair the regeneration capacity of LSCs in the patient-derived leukemia xenograft mouse model. Mechanistically, anlotinib inhibited phosphorylation of c-kit, JAK2/STAT3, and STAT5, and downregulated STAT3 and STAT5 expression. In addition, anlotinib downregulated the anti-apoptotic proteins Bcl-2 and Bcl-xL, and upregulated Bax, thereby enhancing the sensitivity of LSCs to idarubicin in vitro. Intriguingly, anlotinib could also partially rescue the interferon-g production of T cells cocultured with LSCs by downregulating PD-L1 expression. In conclusion, anlotinib showed anti-LSC activity and the potential to enhance the sensitivity to idarubicin and inhibit the immunosuppressive feature of LSCs via JAK2/STAT signaling pathway downregulation in the preclinical study. Our results provided a rational basis for combinatory strategies involving anlotinib and chemotherapy or immunotherapy.
... CSCs from hematological malignancies, such as AML, demonstrated aberrant activation of JAK/STAT signaling. 124 The tumor-formation ability of AML CSCs was potently inhibited in immunodeficient mice following JAK1/2 inhibitor treatment, 125 reinforcing the promoting effect of JAK/STAT signaling on CSC stemness across a wide panel of cancers. 126 The role of the JAK/STAT pathway in CSC regulation is best characterized by its tumor-initiating effect in glioblastoma. ...
Cancer stem cells (CSCs) are defined as a subpopulation of malignant tumor cells with selective capacities for tumor initiation, self‐renewal, metastasis, and unlimited growth into bulks, which are believed as a major cause of progressive tumor phenotypes, including recurrence, metastasis, and treatment failure. A number of signaling pathways are involved in the maintenance of stem cell properties and survival of CSCs, including well‐established intrinsic pathways, such as the Notch, Wnt, and Hedgehog signaling, and extrinsic pathways, such as the vascular microenvironment and tumor‐associated immune cells. There is also intricate crosstalk between these signal cascades and other oncogenic pathways. Thus, targeting pathway molecules that regulate CSCs provides a new option for the treatment of therapy‐resistant or ‐refractory tumors. These treatments include small molecule inhibitors, monoclonal antibodies that target key signaling in CSCs, as well as CSC‐directed immunotherapies that harness the immune systems to target CSCs. This review aims to provide an overview of the regulating networks and their immune interactions involved in CSC development. We also address the update on the development of CSC‐directed therapeutics, with a special focus on those with application approval or under clinical evaluation. The major signaling pathways that regulate CSCs. Amongst an array of signaling pathways aberrantly activated in cancer Wnt, JAK/STAT, PI3k/Akt/mTOR, Notch, NF‐κB, Hedgehog, and TGF‐β/Smad pathways are crucial for the of self‐renewal, cell growth, metastasis of CSCs, and angiogenesis.
... 38,55 In humans, a constitutive increase in STAT3/5 via JAK/STAT signaling is reported in LSCs, particularly from high-risk AML, where it is essential for LSC maintenance and self-renewal. 56 Inhibition of STAT3/5 via growth factor receptors, ie, FLT3 and c-KIT, was found to impair AML cell growth and survival. 52,57 Our data indicate that O-GlcNAcylation mediates DC differentiation via STAT3/5 signaling (Fig. 7). ...
Myeloid differentiation blockage at immature and self-renewing stages is a common hallmark across all subtypes of acute myeloid leukemia (AML), despite their genetic heterogeneity. Metabolic state is an important regulator of hematopoietic stem cell (HSC) self-renewal and lineage-specific differentiation as well as several aggressive cancers. However, how O-GlcNAcylation, a nutrient-sensitive posttranslational modification of proteins, contributes to both normal myelopoiesis and AML pathogenesis remains largely unknown. Using small molecule inhibitors and the CRISPR/Cas9 system, we reveal for the first time that inhibition of either OGA or OGT, which subsequently caused an increase or decrease in cellular O-GlcNAcylation, inhibits the self-renewal and maintenance of CD34 + hematopoietic stem/progenitor cells (HSPCs) and leukemic stem/progenitor cells and drives normal and malignant myeloid differentiation. We further unveiled the distinct roles of OGA and OGT inhibition in lineage-specific differentiation. While OGT inhibition induces macrophage differentiation, OGA inhibition promotes the differentiation of both CD34 + HSPCs and AML cells into dendritic cells (DCs), in agreement with an upregulation of a multitude of genes involved in DC development and function and their ability to induce T cell proliferation, via STAT3/5 signaling. Our novel findings provide significant basic knowledge that could be important in understanding AML pathogenesis and overcoming differentiation blockage-agnostic to the genetic background of AML. Additionally, the parallel findings in normal HSPCs may lay the groundwork for future cellular therapy as a means to improve the ex vivo differentiation of normal DCs and macrophages.
... For example, in contrast to the transcriptomic signature of LSCs from patients with intermediate prognoses, CD34 + CD123 + CD3 − CD19 − LSCs harvested from drug-resistant primary AML cells in patients harboring poor-risk prognosis with TP53 alterations (TP53Alt) are enriched for anomalously activated STAT3 transcription factor signaling [126]. Indeed, the JAK/STAT signaling axis, specifically STAT3, promotes "stemness" in cancer stem cells and drives resistance to chemotherapy and radiotherapy, not only in AML, but also in other malignancies such as myxoid liposarcoma and colorectal cancer [127][128][129][130]. Other dysregulated transcriptomic networks underlying AML LSC-mediated therapy resistance and survival include the canonical nuclear factor κB (NFκB) pathway [131,132], depletion of the transcription factor GLI3 in the hedgehog signaling pathway [133][134][135], and c-Myc dysregulation [136]. ...
Notoriously known for their capacity to reconstitute hematological malignancies in vivo, leukemic stem cells (LSCs) represent key drivers of therapeutic resistance and disease relapse, posing as a major medical dilemma. Despite having low abundance in the bulk leukemic population, LSCs have developed unique molecular dependencies and intricate signaling networks to enable self-renewal, quiescence, and drug resistance. To illustrate the multi-dimensional landscape of LSC-mediated leukemogenesis, in this review, we present phenotypical characteristics of LSCs, address the LSC-associated leukemic stromal microenvironment, highlight molecular aberrations that occur in the transcriptome, epigenome, proteome, and metabolome of LSCs, and showcase promising novel therapeutic strategies that potentially target the molecular vulnerabilities of LSCs.
... This STAT protein family consists of transcription factors that interfere with proliferation, differentiation, and apoptosis. Previous research has shown that STAT3 and STAT5 are constitutively activated in AML leukemic blasts, which is not seen in HSCs [93] . This may contribute to the uncontrolled proliferation of these blasts and resistance to chemotherapy-induced apoptosis. ...
In acute myeloid leukemia (AML), a small cell population that contains stem cell features such as lack of differentiation, self-renewal potential, and drug resistance, can be identified. These so-called leukemic stem cells (LSCs) are thought to be responsible for relapse initiation after initial treatment leading to successful eradication of the bulk AML cell population. Since many studies have aimed to characterize and eliminate LSCs to prevent relapse and increase survival rates of patients, LSCs are one of the best characterized cancer stem cells. The specific elimination of LSCs, while sparing the healthy normal hematopoietic stem cells (HSCs), is one of the major challenges in the treatment of leukemia. This review focuses on several surface markers and intracellular transcription factors that can distinguish AML LSCs from HSCs and, therefore, specifically eliminate these stem cell-like leukemic cells. Moreover, previous and ongoing clinical trials of acute leukemia patients treated with therapies targeting these markers are discussed. In contrast to knowledge on LSCs in AML, insight into LSCs in acute lymphoid leukemia (ALL) is limited. This review therefore also addresses the latest insight into LSCs in ALL.
... downstream signal transducer and activator of transcription (STAT) factors [22][23][24]. STATs, particularly STAT3 and STAT5, are hyperactivated in various solid tumors and hematological malignancies stimulating cellular proliferation and survival [25][26][27][28][29][30][31]. STAT3 and STAT5 are constitutively activated in 44-76% of AML patients [32-34] and individuals show a shorter diseasefree survival with constitutive STAT3 activity than without [33]. ...
Aberrant Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling is implicated in the pathogenesis of acute myeloid leukemia (AML), a highly heterogeneous hematopoietic malignancy. The management of AML is complex and despite impressive efforts into better understanding its underlying molecular mechanisms, survival rates in the elderly have not shown a substantial improvement over the past decades. This is particularly due to the heterogeneity of AML and the need for personalized approaches. Due to the crucial role of the deregulated JAK-STAT signaling in AML, selective targeting of the JAK-STAT pathway, particularly constitutively activated STAT3 and STAT5 and their associated upstream JAKs, is of great interest. This strategy has shown promising results in vitro and in vivo with several compounds having reached clinical trials. Here, we summarize recent FDA approvals and current potential clinically relevant inhibitors for AML patients targeting JAK and STAT proteins. This review underlines the need for detailed cytogenetic analysis and additional assessment of JAK-STAT pathway activation. It highlights the ongoing development of new JAK-STAT inhibitors with better disease specificity, which opens up new avenues for improved disease management.
... Benekli et al. reported constitutive STAT3 activation in 44% of AML patients coincident with unfavorable clinical outcomes [54]. Many studies have linked the aberrant JAK/STAT signaling with leukemia initiation and progression [47,[55][56][57]. More recently, the gain-of-function mutations in JAK1, JAK2, and JAK3 were identified in various leukemia subtypes [58][59][60][61]. ...
... Altogether, a growing body of evidence underscores the importance of JAK/STAT activation in leukemogenesis. Thus, targeting aberrant JAK/STAT signaling has been considered an attractive strategy in targeting leukemic cells [2,56,57,[63][64][65][66][67]. In addition to the profound role of genetic alterations in JAK/STAT activation, the aberrant activation of this pathway is also seen in leukemias that do not harbor mutations in JAK/STAT or IL7 receptor, suggesting that there are other mechanisms activating this pathway. ...
Cytokines are pleiotropic signaling molecules that execute an essential role in cell-to-cell communication through binding to cell surface receptors. Receptor binding activates intracellular signaling cascades in the target cell that bring about a wide range of cellular responses, including induction of cell proliferation, migration, differentiation, and apoptosis. The Janus kinase and transducers and activators of transcription (JAK/STAT) signaling pathways are activated upon cytokines and growth factors binding with their corresponding receptors. The SOCS family of proteins has emerged as a key regulator of cytokine signaling, and SOCS insufficiency leads to constitutive activation of JAK/STAT signaling and oncogenic transformation. Dysregulation of SOCS expression is linked to various solid tumors with invasive properties. However, the roles of SOCS in hematological malignancies, such as leukemia, are less clear. In this review, we discuss the recent advances pertaining to SOCS dysregulation in leukemia development and progression. We also highlight the roles of specific SOCS in immune cells within the tumor microenvironment and their possible involvement in anti-tumor immunity. Finally, we discuss the epigenetic, genetic, and post-transcriptional modifications of SOCS genes during tumorigenesis, with an emphasis on leukemia.
... As previously reported, deprivation of cytokines such IL-3, G-CSF, SCF could induce gradual loss of stemness of LSC 16 . Accordingly, the phenotypic features such IL-3 receptor (CD123) and IL-2 receptor (CD25) high expression confer its capacity to receive cytokines signaling 4,9,11 . Recently, et al reported LSC displayed high expression of multiple growth factor receptors such c-kit, FMS-related tyrosine kinase 3(FLT3), which incurred the overactivation of their downstream tyrosine kinases such as Janus kinase 2 (JAK2) 4 . ...
... Accordingly, the phenotypic features such IL-3 receptor (CD123) and IL-2 receptor (CD25) high expression confer its capacity to receive cytokines signaling 4,9,11 . Recently, et al reported LSC displayed high expression of multiple growth factor receptors such c-kit, FMS-related tyrosine kinase 3(FLT3), which incurred the overactivation of their downstream tyrosine kinases such as Janus kinase 2 (JAK2) 4 . The JAK family of nonreceptor tyrosine kinases are critical mediators of cytokines and growth factor signaling 12 and represent an important signaling mechanism supporting AML LSC growth and survival 2 . ...
Leukemia stem cells (LSCs) remain as the critical barrier to cure of acute myeloid leukemia (AML) due to its chemoresistance. Here, we explore the role anlotinib -a multiple tyrosine kinases inhibitor in killing LSCs and regulating the chemoresistance. We found anlotinib could effectively induce apoptosis of LSC-like cells as well as primary CD34+ AML LSCs while sparing the normal mononuclear cells in vitro. The anti-leukemia activity of anlotinib was also confirmed in the mice model with Kasumi-1 cells; we further found that anlotinib could impair the regeneration capacity of LSCs in the patient-derived leukemia xenograft mouse model. Mechanistically, anlotinib could not only inhibit phosphorylation of c-kit and JAK2 /STAT3 and STAT5 but also downregulate STAT3 and STAT5 expression. In addition, anlotinib downregulated the anti-apoptotic protein Bcl-2 and Bcl-xl and upregulated Bax, thereby enhancing the sensitivity of LSCs to idarubicin in vitro. In conclusion, our results demonstrated anlotinib showed anti-LSCs activity and enhanced the chemosensitivity via inhibiting JAK2/STAT signaling in preclinical study and provided a rational basis for combinatory strategies that invoving anlotinib and idarubicin.
