Disturbed <scp>CXCR</scp>4/<scp>CXCL</scp>12 axis in paediatric precursor B‐cell acute lymphoblastic leukaemia

Berk, Lieke C. J. van den; Veer, Arian van der; Willemse, Marieke E.; Theeuwes, Myrte; Luijendijk, Mirjam W.J.; Tong, Wing H.; Sluis, Inge M. van der; Pieters, Rob; Boer, Monique L. den

doi:10.1111/bjh.12883

Cited by 68 publications

(67 citation statements)

References 41 publications

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“…Nevertheless, our results suggest that upregulation of CXCR4 is a mechanism of therapy resistance in relapsed TCF3-PBX1 BCP-ALL. Similar observations have been made in BCP-ALL 19 as well as pediatric AML, 20 and provide a rationale for targeting CXCR4 either by direct antagonists such as plerixafor 21 or by downstream inhibitors of CXCR4 signaling such as dasatinib. 22 In CLL, idelalisib inhibits chemokine receptor signaling in leukemia cells causing mobilization of leukemia cells into the bloodstream, which manifests clinically as transient lymphocytosis.…”

Section: Discussionsupporting

confidence: 70%

Idelalisib sensitivity and mechanisms of disease progression in relapsed TCF3-PBX1 acute lymphoblastic leukemia

Eldfors¹,

Kuusanmäki²,

Kontro³

et al. 2016

European Journal of Cancer

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Section: Discussionsupporting

confidence: 70%

Idelalisib sensitivity and mechanisms of disease progression in relapsed TCF3-PBX1 acute lymphoblastic leukemia

Eldfors¹,

Kuusanmäki²,

Kontro³

et al. 2016

European Journal of Cancer

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“…MSCs were processed as described previously. 32 Primary MSCs were characterized using positive (CD44/CD90/CD105/CD54/CD73/ CD146/CD166/STRO-1) and negative (CD19/CD45/CD34) surface markers (supplemental Figure 6). Multilineage potential of MSCs was confirmed for adipocyte (Oil Red O staining), osteocyte (Alizarin Red S staining), and chondrocyte (Col2a/Thionine/Alcian Blue staining) differentiation.…”

Section: Primary Patient-derived Materialsmentioning

confidence: 99%

B-cell precursor acute lymphoblastic leukemia cells use tunneling nanotubes to orchestrate their microenvironment

Polak

Rooij

Pieters

et al. 2015

Blood

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150

165

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Key Points• Primary BCP-ALL cells use tunneling nanotubes to signal to mesenchymal stromal cells and thereby trigger cytokine secretion.• Inhibiting tunneling nanotube signaling is a promising approach to induce apoptosis and sensitize BCP-ALL cells toward prednisolone.Acute lymphoblastic leukemia (ALL) cells reside in the bone marrow microenvironment which nurtures and protects cells from chemotherapeutic drugs. IntroductionAcute lymphoblastic leukemia (ALL) cells reside in the local microenvironment of the bone marrow and are able to disrupt normal hematopoietic stem cell niches.1 The disrupted, so-called leukemic, niche is essential in initiating and facilitating leukemogenesis. [2][3][4][5][6] In addition, the leukemic niche protects leukemic cells from elimination by immune responses and chemotherapeutic agents, and can facilitate the development of drug resistance of leukemic cells.7-10 Therefore, the disruption of the ALL-leukemic niche interaction offers a promising new therapeutic strategy.11-16 However, it is still largely unclear how crosstalk occurs within the leukemic niche, and how this drives leukemic cell survival and chemotherapy resistance.Recently, tunneling nanotubes (TNTs), or membrane nanotubes, have been described as a novel mode of communication between eukaryotic cells. [17][18][19][20][21] TNTs are thin membrane protrusions consisting of F-actin, that connect cells and facilitate the transport of several types of cargo, including organelles, pathogens, calcium fluxes, death signals, and membrane-bound proteins. 19,20,[22][23][24] These intercellular membrane conduits have been observed in several cell types, like cancer cells, complex tissues, and organisms. 20,21,[24][25][26][27][28][29] The pathophysiological importance of TNTs has become evident by studies showing that prions and HIV-1 particles use TNTs to promote disease spread. 21,30 However, the presence of TNTs within the leukemic niche and hence their role in communication between leukemic cells and the bone marrow microenvironment has not yet been addressed. Here, we study the role of TNT signaling in communication between primary B-cell precursor ALL (BCP-ALL) cells and mesenchymal stromal cells (MSCs), and the contribution of TNT signaling to mesenchymal-mediated survival and resistance to the chemotherapeutic drug prednisolone. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734. For personal use only. on May 12, 2018. by guest www.bloodjournal.org From Primary patient-derived materialBone marrow aspirates were obtained from children with newly diagnosed BCP-ALL prior to treatment. Mononuclear leukemic cells were collected and processed as previously described. 31 All samples used in this study contained $97% leukemic blasts (supplemental Figure 7, see supplemental Data available at the Blood Web site). MSCs were isolated from bone marrow aspirates obtained from n...

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“…Reverse phase protein arrays were performed as described previously [37][38][39][40] in collaboration with E. Petricoin (George Mason University). The experimental procedure and analysis are described in supplemental Methods.…”

Section: Western Blotting and Reverse Phase Protein Arraysmentioning

confidence: 99%

“…Western blotting was performed with appropriate dilutions of primary antibodies followed by incubation with IRDye secondary antibodies (Pierce) and detected using the Odyssey system (LI-COR Biosciences). The antibodies used are listed in supplemental Table 7.Reverse phase protein arrays were performed as described previously [37][38][39][40] in collaboration with E. Petricoin (George Mason University). The experimental procedure and analysis are described in supplemental Methods.…”

mentioning

confidence: 99%

The role of the Janus-faced transcription factor PAX5-JAK2 in acute lymphoblastic leukemia

Schinnerl

Fortschegger

Kauer

et al. 2015

Blood

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Key Points• PAX5-JAK2 is the first nuclear DNA-binding JAK2 fusion protein with kinase activity.• JAK2 inhibitors block the kinase activity of PAX5-JAK2.PAX5-JAK2 has recently been identified as a novel recurrent fusion gene in B-cell precursor acute lymphoblastic leukemia, but the function of the encoded chimeric proteinhas not yet been characterized in detail. Herein we show that the PAX5-JAK2 chimera, which consists of the DNA-binding paired domain of PAX5 and the active kinase domain of JAK2, is a nuclear protein that has the ability to bind to wild-type PAX5 target loci. Moreover, our data provide compelling evidence that PAX5-JAK2 functions as a nuclear catalytically active kinase that autophosphorylates and in turn phosphorylates and activates downstream signal transducers and activators of transcription (STATs) in an apparently noncanonical mode. The chimeric protein also enables cytokine-independent growth of Ba/F3 cells and therefore possesses transforming potential. Importantly, the kinase activity of PAX5-JAK2 can be efficiently blocked by JAK2 inhibitors, rendering it a potential target for therapeutic intervention. Together, our data show that PAX5-JAK2 simultaneously deregulates the PAX5 downstream transcriptional program and activates the Janus kinase-STAT signaling cascade and thus, by interfering with these two important pathways, may promote leukemogenesis. (Blood. 2015;125(8):1282-1291 IntroductionThe fusion protein PAX5-JAK2 has been recurrently detected in B-cell precursor acute lymphoblastic leukemia (BCP-ALL).1-4 Both fusion partner proteins play key roles in hematopoiesis, and somatic mutations in their encoding genes have been found in different hematologic neoplasms. 5-7The paired box transcription factor PAX5, a master regulator of B-cell commitment and maintenance, 6 is a frequent target of genetic alterations in BCP-ALL. 5,8 In ;2% to 3% of the cases, structural rearrangements result in the expression of PAX5 in-frame fusion genes. 1,2,4,5,[8][9][10] PAX5 fusion partners comprise a heterogeneous group of genes encoding transcription factors, structural proteins, kinases, and genes with thus far unknown functions. 1,2,8,9,[11][12][13] Regardless of the functional and structural diversity of the fusion partners, a unique feature of PAX5 fusions is the retention of the PAX5 DNA-binding domain, conferring nuclear localization and the ability to occupy PAX5 target sites. 14 Generally, it is hypothesized that PAX5 fusions act as aberrant transcription factors antagonizing wild-type PAX5 function in a dominant negative mode. 1,8,9,11,[15][16][17][18] However, in a recent study, we have shown that a subset of the PAX5 fusion proteins may have a cellular context-dependent activation potential, indicating that some PAX5 fusions may also activate target genes, thus arguing against their simplified trans-dominant negative function. 14 Janus kinase 2 (JAK2) belongs to a family of nonreceptor tyrosine kinases and is involved in signal transduction from many cytokine and growth hormone receptors ...

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Disturbed CXCR4/CXCL12 axis in paediatric precursor B‐cell acute lymphoblastic leukaemia

Cited by 68 publications

References 41 publications

Idelalisib sensitivity and mechanisms of disease progression in relapsed TCF3-PBX1 acute lymphoblastic leukemia

Idelalisib sensitivity and mechanisms of disease progression in relapsed TCF3-PBX1 acute lymphoblastic leukemia

B-cell precursor acute lymphoblastic leukemia cells use tunneling nanotubes to orchestrate their microenvironment

The role of the Janus-faced transcription factor PAX5-JAK2 in acute lymphoblastic leukemia

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