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«3. Medizinische Klinik und Poliklinik – Hämatologische Forschung Cks1 is a critical regulator of hematopoietic stem cell cycling, quiescence and ...»

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Growth factors and cytokines A vast number of growth factors and cytokines promoting hematopoiesis is produced in the HSC niche environment. For instance, granulocyte colonystimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), interleukin 6 (IL6), FMS related tyrosine kinase 3 ligand (Flt3L) and stem cell factor (SCF) are expressed in the bone marrow endothelial cells [56, 57]. SCF, which binds and activate the c-Kit receptor, plays an important role in maintaining the long term repopulating activity of HSC [58, 59]. In the bone marrow, SCF is also being produced in osteoblastic cells and nestin-expressing mesenchymal stromal cells (MSC) [57]. Osteoblastic cells express other important factors for maintenance of the long term repopulating activity and quiescence in HSC such as thrombopoietin (TPO) and angiopoietin 1 (Ang-1), whereas Ang-1 is also expressed in nestin-expressing MSC [57]. Some inflammatory cytokines are also playing role in regulating HSC, like the chemokine C-X-C motive chemokine 12 (CXCL12), which is expressed in CXCL12-abundant reticular cells (so called CAR cells), nestin expressing MSC, osteoblastic cells and endothelial cells. CXCL12 regulates the pool size, the homing and the retention of HSC [57, 60, 61].

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immune system, tumor development and angiogenesis. TGF-β plays a key role in regulating HSC [62, 63]. TGF-β exists in three isoforms, TGF-β1, TGF-β2 and TGF-β3, which bind to two different receptors, TβRI and TβRII and activate intracellular proteins, so called Smads. Smads are organized in two branches Smad2/3 and Smad 1/5/8, which transduce the TGF-β signal downstream to Smad4, which translocates to the nucleus and activates gene transcription [62].

A number of studies prove that TGF-β signaling can maintain HSC quiescence during steady state hematopoiesis [63-68].

Pten/Akt pathway Protein kinase B (Akt) signaling, the so called phosphatidylinositol-3-OH kinase (PIK3)-Akt pathway is activated by growth factors and regulates proliferation, survival, growth, metabolic functions and resistance to stress. The phosphatase and tensin homolog (Pten) negatively regulates the PIK3-Akt pathway by inhibiting the activation of Akt. [62]. Pten and Akt have been shown to be important regulators of hematopoiesis and HSC. Pten influences the LT-HSC pool and loss of Pten leads to myeloproliferative disorder [69-71], while both members of the Akt family, Akt1 and Akt2, are essential for maintaining the HSC functions [72]. Furthermore, a downstream target in the Pten/Akt pathway, Forkhead box O (FoxO) transcription factor, is also a significant regulator of the HSC pool, self-renewal and reconstitution ability [73, 74].

Wnt pathway The Wnt protein family include secreted ligand molecules, which can bind to surface receptors and subsequently induce canonical and noncanonical branches of the Wnt- dependent pathway [62]. Wnt sinaling is highly important in emryogenesis and tumorigenesis [75]. A vast number of research in the field of Wnt signaling and hematopoiesis demonstrate the significance of the Wnt pathway in regulating the HSC. For instance, the canonical Wnt signaling is shown to be important for regulation of proliferation and maintenance of the HSC through the niche [76]. Besides, loss of β-catenin, a protein downstream in the canonical pathway, leads to decreased long-term repopulation efficiency of HSC [77]. Furthermore, Sugimura et. al. demonstrate, that the noncanonical Wnt-signalling maintains HSC in the niche [78].


1.2.3. Regulation of the cell cycle in HSC An essential characteristic of the HSC is the balance between dormancy and active cycling. Depending on cell extrinsic and cell intrinsic factors, HSC can remain quiescent, self-renew, differentiate, migrate or die. In a steady state condition adult HSC are most of the time quiescent [79]. HSC are constantly required to replenish the blood system since mature blood cells have a short life span [42]. Also, in case of injuries and other hematopoietic stress conditions, quiescent HSC are induced upon external and internal signals to enter the cell cycle [42, 80]. The intrinsic mechanisms regulating the cell cycle in HSC include Cyclin/CDK complexes, Rb proteins and CKI and are together with the extrinsic factors subject of intensive research (Fig. 1).

Studies of knockout mice for the protein of interest deliver knowledge about the role of the different cell cycle regulators in the complex hematopoietic machinery. Mice, that lack cell cycle regulators, display modest to severe phenotypes which affect different levels of the HSC/HPC hierarchy [11, 12, 81].

Cyclin/CDK complexes Since activating the switch from dormancy to cell division involves entering the cell cycle in G1 phase, the G0-G1 checkpoint is the most important part of HSC regulation. Progression to G1 is controlled by CDK4 and CDK6 kinases and the cyclin D family members cyclin D1, cyclin D2 and cyclin D3 [82]. Knockout mice for all three cyclin D family members die during embryogenesis because of heart defects and hematopoietic failure [83]. The absolute numbers and the frequency of cycling HSC and HPC cells are reduced in cyclin D1/2/3-/- fetal liver (FL), where at embryonic days 13-14 the massive production of various fetal HSC cells occurs [83, 84]. Furthermore, cyclin D1/2/3-/- FL cells could not reconstitute irradiated recipient mice [83] while one of the most important HSC characteristics is the ability to long-term reconstitute the hematopoietic system in irradiated host [85]. Double knockouts for CDK4/CDK6 display similar defects in the FL hematopoiesis as the cyclin D knockouts [86]. In contrast, CDK2 and CDK6 loss together or separately seem not to play a role in adult HSC regulation [86, 87].


Rb family The Rb family members (pRb, p103 and p107) play an essential role in progression through G1 phase. Only upon phosphorylation by cyclin D-CDK4/6 complexes and releasing the inhibitory effect of Rb family members on E2F transcription factors, target genes that are necessary for the progression through G1 can be expressed [8]. Interestingly, deleting only one of the family members did not result in severe defects [82, 88-90]. Though a triple knockout mouse for all three family members led to death of the animals at week 4-12 after gene inactivation caused by myeloid expansion. The triple pRb, p107 and p103 knockout HSC were increased in absolute cell number, exhibited severe defects in self-renewal and highly impaired reconstitution potential [91].

CKI from the INK4 family Studies with knockout mice for different members of the INK4 family, demonstrate, that p16, p18 and p19 are differentially regulated in HSC to maintain balance between quiescence and proliferation [32, 82]. Deletion of both p16 and p19 has no severe effect on HSC activity [82], whereas HSC lacking p18 display elevated engraftment capability in serial transplantations [92]. Nevertheless, a regulation of the HSC by p16 was demonstrated in older mice, where loss of p16 led to increase in the HSC pool [92, 93].

CKI from the CIP/KIP family Since CKI from the CIP/KIP family also regulate the entry into G1, their effects on HSC regulation has also been an attractive target for investigation. Reports from mutant mouse strains have demonstrated that although all members are involved in the regulation of quiescence of hematopoietic cells under steady state conditions [94], the main function of the CIP/KIP family members appears to be the regulation of cell cycle during periods of hematopoietic stress [95, 96].

For instance, p21 was associated with regulation of HSC at the entry into the cell cycle [97], though a more recent study demonstrates a role of p21 in conditions of stress and DNA damage [98]. Another CIP/KIP family member, p27, has been shown to be important for regulation of cell cycle activity of more committed HPC and lack of p27 alone did not affect HSC number or cycling [99]. In contrast, p57 seem to play a key role in regulating HSC and p57


expression is shown to be highest in this early subpopulation of hematopoietic cells [100, 101]. Conditional deletion of p57 in hematopoietic cells resulted in decreased adult HPC pool and loss of HSC quiescence demonstrating, that p57 is a critical mediator of HSC quiescence [100]. Also, the p57-/- phenotype could be compensated with overexpression of p27, but not p21 [100, 101].

Interestingly, p21 and p57 seem to be direct targets for growth repressive signals, such as TGF-β, demonstrating a role of the hematopoietic niche in CKI regulation [102]. In particular, the regulation of the HSC quiescence through p57 and p27 seems to take place upstream of the Rb family [101]. Taken together, these studies implicate overlapping and unique roles of different CIP/KIP family members in regulation of HSC.

The vast number of studies on cell cycle regulators such as CKI and Rb family members reveal in general, that loss of cell cycle inhibitors lead to increased cycling and decreased quiescence in HSC and therefore to loss or decrease of self-renewal potential.

1.2.4. Chronic myeloid leukemia, a HSC disease Cancer of the blood or bone marrow is characterized by an abnormal proliferation and increase of white blood cells. Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder, which originates from a HSC and is caused by the so called Philadelphia chromosome [103-105]. The Philadelphia chromosome is generated by a reciprocal translocation between the Abelson (ABL) gene on chromosome 9 and the brake point cluster region (BCR) on chromosome 22, creating BCR-ABL, a hybrid oncogene coding for the BCRABL protein, a constitutively active tyrosine kinase [106-108]. Deregulated signaling through the BCR-ABL kinase leads to uncontrolled increase in proliferation and survival of leukemic cells. Chronic phase of CML is characterized by an increase of predominantly myeloid precursors, which differentiate to abnormal numbers of granulocytes [109]. Untreated chronic phase leads to the accelerate phase, where irregular amount of progenitor/precursor cells are generated, followed by a terminal phase, called blast crisis [109]. The blast crisis is defined by expansion of myeloid or lymphoid

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differentiation-arrested blast cells, presence of immature cells in the blood and lower response to treatment [109, 110].

Currently there are several tyrosine kinase inhibitors applied in the treatment against CML [111]. Imatinib (also STI571 or Gleevec), for instance, is a first generation tyrosine kinase inhibitor, which acts by binding to the catalytic side of BCR-ABL and prevents initiation of the signaling pathway [112]. Imatinib is used successfully to treat patients in the chronic phase of CML since 2001 but may have to be applied through a lifetime, since it does not always cure CML, but only inhibits the proliferation of the leukemic cells [113]. Also, in some cases resistance against imatinib is developed [111]. Quiescent leukemic stem cells are very often insensitive against the drug and capable to sustain CML by providing a pool of leukemic cells [114-116]. Second class tyrosine kinase inhibitors are more specific against progenitors, but also do not always cure the disease and resistances are still possible [111]. Thus, since uncontrolled HSC/HPC regenerative activity is a hallmark of CML and often the cause for resistance against the common drugs, it is important to investigate the driving forces in these cells in order to target CML stem cells for providing cure against the disease.

1.3. SCFSkp2-Cks1

CDK-regulatory subunit 1 (CKS1), a small 9 kDa protein, is a member of the Suc1 (suppressor of Cdc2 mutation)/Cks family and was discovered in budding yeast [117] as a homolog of the Suc1 gene, which was found in fission yeast [118]. Suc1 and Cks1 are shown to exhibit high affinity against CDK1 [119, 120] and to regulate the cell cycle and especially mitosis [118, 121]. Mutant Cks1 deprived of its function results in severe G1/S and G2/M transition defects as well as in mitotic failure in yeast and Xenopus extracts [121, 122].

The Cks family in mammalian cells consists of two members, Cks1 and Cks2, [123]. Concomitant loss of both proteins is lethal for mouse embryos at very early stage [124]. Isolation and analysis of human Cks proteins revealed, that Cks1 and Cks2 are highly conserved in eukaryotes and possess affinity against CDK1, CDK2 and CDK3 [123]. More precisely, Cks1 seems to affect the activity of cyclin-CDK1 towards specific targets [125] and enhances phosphorylation of


some CDK1 substrates [120, 125]. Another significant role of Cks proteins in mitosis involves checkpoint independent anaphase-promoting complex/cyclosome (APC/C) control through targeting cyclin A/CDC20 complexes [126]. Additionally, it was demonstrated that Cks1 is important for targeting cyclin B to the proteasome for degradation in budding yeast [127].

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