HemaBites showcase hematology news and short commentaries on recent high-impact articles published in international journals. This blog will keep you up to date with the latest developments and discoveries in the field of hematology.

Wednesday, July 18, 2018

Catching some rays: UV damage protection in fish hematopoietic stem cells.
Michael D. Milsom1,2
1. Division of Experimental Hematology, German Cancer Research Center (DKFZ), Heidelberg Germany.
2. Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany.

Kidney_Milsom.pngThe hematopoietic system is particularly sensitive to the action of DNA damaging agents, as evidenced by the fact that myelosuppression is frequently observed in humans upon exposure to ionizing radiation or DNA-damaging chemotherapeutic drugs such as alkylating agents. Indeed, multiple lines of experimental investigation have shown that it is important to protect hematopoietic stem and progenitor cells (HSPCs) from DNA damage in order to avoid both short and long-term adverse effects, such as bone marrow failure and leukemic transformation. In a recently published study, the Zon group have uncovered a mechanism that has evolved in fish in order to protect their HSPCs from the ultraviolet (UV) irradiation co​ntained within sunlight. Unlike in mammals, where the primary location of the adult HSPC niche is within the bone marrow, the adult HSPCs of many fish species reside predominantly within the kidney marrow. Kapp and colleagues made the observation that an umbrella-like structure of melanocytes exists above the kidney marrow in a range of species of fish. They were able to show that this umbrella does indeed protect HSPCs from UVB-induced DNA damage, and is important for sustaining production of mature blood cells. The authors speculate that the need to protect HSPCs from UV damage may explain why the mammalian HSPC niche is located within bones.

Image provided by Leonard Zon and Nymus3D

Animated video explaining the work: https://www.youtube.com/watch?v=e6-CrJOr8zY 

Link and full citation of article:
Kapp F.G., et al., Protection from UV light is an evolutionarily conserved feature of the hematopoietic niche. 2018, Nature, 558(7710): pp445-448

Tuesday, July 17, 2018

The portrait of the CLL epigenome

Melania Tesio
Institute Necker des Enfantes Malades, Paris, France

Chronic lymphocytic leukemia (CLL), the most frequent leukemia in Western countries, is a B-cell derived malignancy. The mutational status of the immunoglobulin heavy chain variable region defines two main disease subtypes (mutated CLL and unmutated CLL), which present distinct clinical behaviors.
In a recent Nature Medicine issue, Renée Beekman and colleagues provided an extensive epigenetic characterization of this malignancy. The researchers integrated genome-wide maps of the DNA methylome, analysis of six histone modification marks, DNA accessibility and RNA sequencing data from 107 primary CLL cases and 5 normal mature B-cell subpopulations (Figure). In addition to providing the CLL-specific regulatory landscape and reference epigenome, this analysis showed that the most aggressive unmutated CLL subtype presents more de-novo accessible regions and active regulatory elements as compared to the less aggressive mutated CLL subtype. This suggests that the chromatin variability associates with CLL clinical-biological heterogeneity, thus potentially harboring prognostic value. By further analyzing the link between genetic and epigenetic changes, the authors discovered that non-coding mutations seem not to be associated with quantitative changes in genomic accessibility, whereas specific somatic mutations (such as MYD88 mutations or trisomy 12) present distinct chromatin configurations. 
Globally, the impressive comprehensive characterization of the CLL epigenome carried out by Beekman and colleagues constitutes a precious resource to understand CLL development and identify novel prognostic and diagnostic parameters.​


Figure legend. Comprehensive characterization of CLL epigenome 

Link to the article:  Beekman R, Chapaprieta V, Russiñol N, Vilarrasa-Blasi R, Verdaguer-Dot N, Martens JHA et al. The reference epigenome and regulatory chromatin landscape of chronic lymphocytic leukemia. Nat Med. 2018 May 21.
doi: 10.1038/s41591-018-0028-4.


Monday, July 16, 2018

Increased risk of lymphoma in JAK kinase inhibitor patients with myelofibrosis.

Jan Cools​
VIB Center for Cancer Biology, Leuven
KU Leuven Center for Human Genetics, Leuven, Belgium

Cover june2018- social media.pngAn European study warns that JAK kinase inhibitor treatment may increase the risk of lymphoma 15-fold in patients with myelofibrosis. The authors assessed two cohorts of 626 and 929 patients with myeloproliferative neoplasms (MPN), including myelofibrosis patients who were receiving treatment with JAK kinase inhibitors (ruxolitinib or fedratinib). The incidence of B-cell lymphoma was >5% in patients treated with JAK inhibitors and <0.5% in patients who did not receive JAK inhibitors. The lymphomas were of aggressive B-cell type, extra-nodal or leukemic with h​igh MYC expression in the absence of MPN-associated mutati​ons. Lymphomas occurring during JAK kinase inhibitor treatment were preceded by a pre-existing B-cell clone in the 3 patients who could be tested, and thus detection of such pre-existing B-cell clone at start of JAK kinase inhibitor treatment may identify individuals at risk.
Edit Porpaczy, et al. Aggressive B-cell lymphomas in patients with myelofibrosis receiving JAK1/2 inhibitor therapy. Blood 2018 (https://doi.org/10.1182/blood-2017-10-810739)

Thursday, July 12, 2018

Platelets exploited?
Roger Schutgens
University Medical Center Utrecht, Utrecht, The Netherlands

Platelets.pngPlatelets play a crucial role in normal hemostasis. Besides hemostasis, they are implicated in atherosclerosis, inflammation, sepsis and cancer. Although platelets have been shown to promote cancer metastasis, the exact cancer cell ligands capable of initiating platelet secretion and aggregation are not well known. Recently, CD97 (a G-protein-coupled receptor) has been identified to activate platelets, leading to the release of adenosine triphosphate (ATP) (1). ATP mediates endothelial junction disruption, facilitating migration of metastatic cancer cells. In addition, CD97 appears to act as a motility receptor for lysophosphatidic acid (LPA) released from platelets. The consequent platelet-derived LPA in proximity to CD97-LPAR heterodimers induces signaling of RHO, producing an invasive phenotype (Figure).
These findings support targeted blockade of tumor CD97 as an approach to prevent metastatic spread. As the receptor for CD97 on platelets has not yet been identified, a search is ongoing for alternative approaches to inhibit platelet activation. However, an important limitation to the use of currently available anti-platelet agents in cancer patients is represented by their bleeding risk and the concomitant thrombocytopenia during chemotherapy. Furthermore, there is evidence that suggests that the regulating mechanisms of platelets in cancer are different from those in hemostasis, and thus anti-platelet agents may not necessarily prevent inflammatory platelet activation effectively (2).

Figure (from Ward et al. (1))
1. Ward Y, Lake R, Faraji F, Sperger J, Martin P, Gilliard C, Ku KP, Rodems T, Niles D, Tillman H, Yin J, Hunter K, Sowalsky AG, Lang J, Kelly K. Platelets Promote Metastasis via Binding Tumor CD97 Leading to Bidirectional Signaling that Coordinates Transendothelial Migration. Cell Rep. 2018 Apr 17;23(3):808-822. doi: 10.1016/j.celrep.2018.03.092
2. Gresele P, Momi S, Malvestiti M, Sebastiano M. Platelet-targeted pharmacologic treatments as anti-cancer therapy. Cancer Metastasis Rev. 2017 Jun;36(2):331-355. doi: 10.1007/s10555-017-9679-8.

Tuesday, June 19, 2018

Stem cell biases enforced by the niche
Michael D. Milsom1,2
1 Division of Experimental Hematology, German Cancer Research Center (DKFZ), Heidelberg Germany.
2 Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany.
Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Various analyses of hemFrenette_Image-small.pngatopoietic stem cells (HSCs) have uncovered evidence of heterogeneity at the molecular and functional level. Such functional heterogeneity includes so-called lineage biases within the HSC compartment, meaning that while lineage-biased HSCs are capable of generating many mature blood cell types, they favour production of some cell lineages over others. However, the underlying mechanism via which such differentiation biases are established remains to be elucidated. A recent article in Developmental Cell has characterized that such biases appear to be reinforced by the exact composition of the HSC niche. Using a transgenic mouse reporter line to prospectively identify platelet and myeloid-biased HSCs, based upon expression level of von Willebrand factor (vWF), they found that the bone marrow niche for these HSCs was megakaryocyte-rich. Selective ablation of megakaryocytes led to an expansion of vWF+ but not vWF- HSCs, demonstrating their specific regulatory effect on this cell type. In contrast, lymphoid-biased HSCs were maintained in quiescence by NG2+ periarteriolar cells that are found in the so-called arteriolar niche. This is the first direct evidence that HSC lineage biases are likely established and maintained by discrete niche components, raising the possibility that the niche may modulate pathologies that could be linked with lineage bias.
Link and full citation of article:
Pinho S., et al., Lineage-Biased Hematopoietic Stem Cells are regulated by Distinct Niches. 2018, Dev. Cell., 44(5):pp634-41

Figure legend (courtesy of Paul Frenette)
Whole-mount confocal image of the sternal bone marrow from a Vwf-eGFP transgenic mouse which where eGFP marks megakaryocytes and a subset of hematopoietic stem cells (HSCs). A putative HSC is shown in red adjacent to a green megakaryocyte with the vasculature shown in blue. Image provided by Paul Frenette, Albert Einstein College of Medicine, The Bronx, NY.