Jak1 Integrates Cytokine Sensing to Regulate Hematopoietic Stem Cell Function and Stress Hematopoiesis

Kleppe, Maria; Spitzer, Matthew H.; Li, Sheng; Hill, Corinne E.; Dong, Lauren; Papalexi, Efthymia; Groote, Sofie De; Bowman, Robert L.; Keller, Matthew D.; Koppikar, Priya; Rapaport, Franck; Teruya‐Feldstein, Julie; Gandara, Jorge; Mason, Christopher E.; Nolan, Garry P.; Levine, Ross L.

doi:10.1016/j.stem.2017.08.011

Cited by 65 publications

(49 citation statements)

References 46 publications

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“…Notably, this transcriptional program was significantly enriched in genes controlled by JAK1 in HSCs (ref. 18; Fig. 3I), supporting a potential convergent transcriptional mechanism between genetic inactivation of Phf6 and JAK-STAT signaling in HSC self-renewal.…”

Section: Phf6 Mutations Are Early Events In Leukemia Transformation Amentioning

confidence: 78%

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Phf6 Loss Enhances HSC Self-Renewal Driving Tumor Initiation and Leukemia Stem Cell Activity in T-ALL

et al. 2019

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The plant homeodomain 6 gene (PHF6) is frequently mutated in human T-cell acute lymphoblastic leukemia (T-ALL); however, its specifi c functional role in leukemia development remains to be established. Here, we show that loss of PHF6 is an early mutational event in leukemia transformation. Mechanistically, genetic inactivation of Phf6 in the hematopoietic system enhances hematopoietic stem cell (HSC) long-term self-renewal and hematopoietic recovery after chemotherapy by rendering Phf6 knockout HSCs more quiescent and less prone to stress-induced activation. Consistent with a leukemia-initiating tumor suppressor role, inactivation of Phf6 in hematopoietic progenitors lowers the threshold for the development of NOTCH1-induced TALL. Moreover, loss of Phf6 in leukemia lymphoblasts activates a leukemia stem cell transcriptional program and drives enhanced TALL leukemia-initiating cell activity. These results implicate Phf6 in the control of HSC homeostasis and long-term self-renewal and support a role for PHF6 loss as a driver of leukemiainitiating cell activity in TALL. SIGNIFICANCE: Phf6 controls HSC homeostasis, leukemia initiation, and TALL leukemia-initiating cell self-renewal. These results substantiate a role for PHF6 mutations as early events and drivers of leukemia stem cell activity in the pathogenesis of TALL .

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Section: Phf6 Mutations Are Early Events In Leukemia Transformation Amentioning

confidence: 78%

“…We used the Jak1 mouse knockout hematopoietic stem cell signature gene set from ref. 18 31. For analysis of mouse tumors, human gene identifiers were converted to mouse in R using the biomaRt bioconductor package.…”

Section: Gene Set Enrichment Analysismentioning

confidence: 99%

Phf6 Loss Enhances HSC Self-Renewal Driving Tumor Initiation and Leukemia Stem Cell Activity in T-ALL

et al. 2019

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“…Accordingly, somatic JAK1 GOF mutations are found in 10-20% of T-cell acute lymphoblastic leukemia (T-ALL) patients [35]. Recently, conditional JAK1 knock-out (KO) mice were developed, and RNA sequencing from isolated hematopoietic stem cells showed that the genes most affected by the loss of JAK1 were STAT1, STAT2, and multiple members of the IFN regulatory transcription family, confirming the important role of JAK1 in regulating these factors [36]. Moreover, it was shown that loss of JAK1 leads to decreased IFNγ sensitivity ex vivo.…”

Section: Discussionmentioning

confidence: 99%

Characterization of JAK1 Pseudokinase Domain in Cytokine Signaling

Raivola

Haikarainen

Silvennoinen

2019

Cancers

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The Janus kinase-signal transducer and activator of transcription protein (JAK-STAT) pathway mediates essential biological functions from immune responses to haematopoiesis. Deregulated JAK-STAT signaling causes myeloproliferative neoplasms, leukaemia, and lymphomas, as well as autoimmune diseases. Thereby JAKs have gained significant relevance as therapeutic targets. However, there is still a clinical need for better JAK inhibitors and novel strategies targeting regions outside the conserved kinase domain have gained interest. In-depth knowledge about the molecular details of JAK activation is required. For example, whether the function and regulation between receptors is conserved remains an open question. We used JAK-deficient cell-lines and structure-based mutagenesis to study the function of JAK1 and its pseudokinase domain (JH2) in cytokine signaling pathways that employ JAK1 with different JAK heterodimerization partner. In interleukin-2 (IL-2)-induced STAT5 activation JAK1 was dominant over JAK3 but in interferon-γ (IFNγ) and interferon-α (IFNα) signaling both JAK1 and heteromeric partner JAK2 or TYK2 were both indispensable for STAT1 activation. Moreover, IL-2 signaling was strictly dependent on both JAK1 JH1 and JH2 but in IFNγ signaling JAK1 JH2 rather than kinase activity was required for STAT1 activation. To investigate the regulatory function, we focused on two allosteric regions in JAK1 JH2, the ATP-binding pocket and the αC-helix. Mutating L633 at the αC reduced basal and cytokine induced activation of STAT in both JAK1 wild-type (WT) and constitutively activated mutant backgrounds. Moreover, biochemical characterization and comparison of JH2s let us depict differences in the JH2 ATP-binding and strengthen the hypothesis that de-stabilization of the domain disturbs the regulatory JH1-JH2 interaction. Collectively, our results bring mechanistic understanding about the function of JAK1 in different receptor complexes that likely have relevance for the design of specific JAK modulators.

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“…This is reminiscent of the STAT-dependent transcriptional induction of pro-survival Bcl-2 family members in mouse cell lines (Catlett-Falcone et al, 1999;Fujio et al, 1997). Indeed, targeted disruption of JAK/STAT signaling in vivo in mice leads to reduced proliferation and decreased survival of multiple cell lineages, including the inner cell mass, and neuronal, hematopoietic and cardiac cells (Do et al, 2013;Kleppe et al, 2017;Levy and Lee, 2002;McLemore et al, 2001;Onishi and Zandstra, 2015;Takeda et al, 1997;Yoshida et al, 1996).…”

Section: Parallels In Jak/stat Signaling Across Tissues and Across Spmentioning

confidence: 94%

JAK/STAT signaling in stem cells and regeneration: fromDrosophilato vertebrates

2019

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The JAK/STAT pathway is a conserved metazoan signaling system that transduces cues from extracellular cytokines into transcriptional changes in the nucleus. JAK/STAT signaling is best known for its roles in immunity. However, recent work has demonstrated that it also regulates critical homeostatic processes in germline and somatic stem cells, as well as regenerative processes in several tissues, including the gonad, intestine and appendages. Here, we provide an overview of JAK/STAT signaling in stem cells and regeneration, focusing on Drosophila and highlighting JAK/STAT pathway functions in proliferation, survival and cell competition that are conserved between Drosophila and vertebrates.

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Jak1 Integrates Cytokine Sensing to Regulate Hematopoietic Stem Cell Function and Stress Hematopoiesis

Cited by 65 publications

References 46 publications

Phf6 Loss Enhances HSC Self-Renewal Driving Tumor Initiation and Leukemia Stem Cell Activity in T-ALL

Phf6 Loss Enhances HSC Self-Renewal Driving Tumor Initiation and Leukemia Stem Cell Activity in T-ALL

Characterization of JAK1 Pseudokinase Domain in Cytokine Signaling

JAK/STAT signaling in stem cells and regeneration: fromDrosophilato vertebrates

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