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PI3K, induced by IPI-145 but not idelalisib, in fact lead to more tumor toxicity in vivo? Similarly, might it reduce the effector functions of various immune effectors when used in combination with mAbs? For these answers, we eagerly await the results of the upcoming trials and further in vitro experimentation. Despite these unresolved questions, this article provides exciting new data and insight into the biology of the PI3K signaling pathway in CLL cells, which will enable the development of more effective drugs for the treatment of this currently incurable disease. Moreover, the more inhibitors we have for the BCR signaling pathway, the more tools we will have to further dissect its critical signaling functions in malignant cells and the more opportunities we will have to explore rational combinations for improved therapeutic efficacy in the future. Conflict-of-interest disclosure: The author declares no competing financial interests. n REFERENCES 1. Dong S, Guinn D, Dubovsky JA, et al. IPI-145 antagonizes intrinsic and extrinsic survival signals in chronic lymphocytic leukemia cells. Blood. 2014;124(24): 3583-3586. 2. Stevenson FK, Krysov S, Davies AJ, Steele AJ, Packham G. B-cell receptor signaling in chronic lymphocytic leukemia. Blood. 2011;118(16):4313-4320. 3. Herman SE, Gordon AL, Wagner AJ, et al. Phosphatidylinositol 3-kinase-d inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood. 2010;116(12):2078-2088. 4. Wodarz D, Garg N, Komarova NL, et al. Kinetics of CLL cells in tissues and blood during therapy with the BTK inhibitor ibrutinib. Blood. 2014;123(26):4132-4135. 5. Woyach JA, Furman RR, Liu TM, et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370(24):2286-2294. 6. Kienle D, Benner A, Kr¨ober A, et al. Distinct gene expression patterns in chronic lymphocytic leukemia defined by usage of specific VH genes. Blood. 2006;107(5):2090-2093. 7. Kulkarni S, Sitaru C, Jakus Z, et al. PI3Kb plays a critical role in neutrophil activation by immune complexes. Sci Signal. 2011;4(168):ra23. 8. Juss JK, Hayhoe RP, Owen CE, et al. Functional redundancy of class I phosphoinositide 3-kinase (PI3K) isoforms in signaling growth factor-mediated human neutrophil survival. PLoS ONE. 2012;7(9):e45933. 9. Hoellenriegel J, Meadows SA, Sivina M, et al. The phosphoinositide 39-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood. 2011;118(13):3603-3612. 10. Tamburini J, Chapuis N, Bardet V, et al. Mammalian target of rapamycin (mTOR) inhibition activates phosphatidylinositol 3-kinase/Akt by up-regulating insulin-like growth factor-1 receptor signaling in acute myeloid leukemia: rationale for therapeutic inhibition of both pathways. Blood. 2008;111(1):379-382. © 2014 by The American Society of Hematology



Comment on Velasco-Hernandez et al, page 3597

Targeting HIF function: the debate continues ----------------------------------------------------------------------------------------------------Paresh Vyas


In this issue of Blood, Velasco-Hernandez et al1 come to an important and at first sight, unexpected, conclusion that hypoxia inducible factor 1a (HIF-1a) may be a tumor suppressor gene.


urrent data suggest leukemic stem cells (LSCs) are adapted to hypoxia, raising the possibility of therapeutic targeting of the transcriptional regulator HIF-1a. Direct oxygen measurement of human marrow shows it has a low overall oxygen partial pressure (;55 mmHg, with an oxygen saturation of 87.5%). Furthermore, perfusion tracer experiments suggest that functional murine hematopoietic stem cells (HSC) are enriched in the lowest perfusion compartment.2 Recent elegant data confirmed what was long suspected: that there is regional variation in vascularization. The central murine marrow diaphysis is poorly vascularized and enriched for cells staining with pimonidazole, a chemical that makes thiol adducts in a low oxygen environment.3 This, coupled with observations that murine HSCs and human LSCs reside next to the endosteum,4,5 support the concept that HSCs and LSCs reside in a particularly hypoxic niche. The heterodimeric transcriptional regulator HIF, which is composed of a and b subunits, mediates, in large part, adaption to hypoxia. There are 3 different a subunits, HIF-1a, HIF-2a, and HIF-3a, and a common HIF-1b subunit. HIF regulates the expression of many genes, which together allow cells to adapt to hypoxia and a low nutrient environment by switching energy production from oxidative to glycolytic pathways and reducing reactive oxygen species production that could have a deleterious mutagenic impact on the genome and promoting quiescence.2 Although all 3 HIF a subunits are expressed in murine HSCs, genetic manipulation of HIF-1a protein levels demonstrates that HIF-1a promotes

murine HSC engraftment and quiescence when tested in transplantation assays and in aged mice.6 In contrast, HIF-2a does not appear to have a similar or additive role in HSCs.7 These observations, coupled with a large amount of literature on HIF function in cancers more generally, have promoted the concept of therapeutic targeting of HIF function. Credence for the notion that HIF-1a may be a therapeutic target in hematologic malignancies has come from in vitro and limited in vivo studies of primary human acute myeloid leukemia (AML) samples, in an experimental murine lymphoma model using the HIF-1a inhibitor echinomycin,8 and in an experimental murine chronic myeloid leukemia model in an HIF-1a2/2 background.9 However, there are also data to support a more important role for HIF-2a, rather than HIF-1a, from knockdown studies that show reduced engraftment when 7 human AML samples were tested.10 Knockdown of HIF-2a also reduced shortand long-term engraftment of primary human CD341 stem/progenitor cells, suggesting more work needs to be done to establish whether there is a therapeutic index for targeting HIF function. Now add into the mix the paper from Cammenga’s laboratory, which asks the following question: is HIF-1a required for leukemic growth in 3 different murine AML models. They studied 3 AML models: a tetracycline inducible human mixed-lineage leukemia (MLL)–eleven nineteen leukemia (ENL) murine knock-in (KI) model and 2 transplantation models where mice were transplanted with bone marrow cells retrovirally transduced with either


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Hoxa9-Meis1 or Aml1-Eto9a. The choice of models was interesting as both MLL-ENL KI and Hoxa9-Meis1 are likely to directly activate HIF-1a through MEIS1 expression, whereas Aml1-Eto9a is not known to signal through HIF-1a. They studied the oncogenes in wild-type cells with Hif-1a alleles or where Hif-1a alleles could be conditionally deleted after engraftment. In all 3 models, the results were clear; there was no dependence on HIF-1a for leukemia initiation, propagation, and leukemia-initiating cell self-renewal in transplantation assays. If anything, the onset of leukemia was accelerated in cells deleted for Hif-1a in the Hoxa9-Meis1 model and when mice were secondarily transplanted with Aml1-Eto9a transduced leukemic cells. One obvious caveat is that compensation by HIF-2a may have obscured a physiologic role for HIF-1a. Although that may be the case, the data do suggest that simply targeting HIF-1a may not be sufficient. Studying AML initiation and propagation in cells with both Hif-1a and Hif-2a conditional alleles would address this question. So where does this leave the field? Although there are still important mechanistic questions about the role of HIF and adaptation to hypoxia by normal stem/early progenitor cells, the bulk of evidence supports a critical role for HIF function in this area. Clearly, more work needs to be done to define any differential functional effects of HIF-1a and HIF-2a between humans and mice. In AML and other hematologic malignancies, the situation is likely to be more complex. The role of HIF (and specifically HIF-a subunits) may depend on a number of parameters. For example, the nature of oncogenic drivers (genetic and epigenetic) is likely to dictate genome integrity and genome robustness. One could hypothesize that loss of HIF function in some malignancies (and AML in particular) may make tumor initiating and propagating cells more vulnerable to genotoxic stress just like their normal hemopoietic stem/early progenitor counterparts, whereas this may not be true in cells with an altered TP53 function. Oncogenic drivers are also likely to influence self-renewal, the need (or lack of) for quiescence, and optimal metabolism for leukemia initiating and propagating cells. Taken together, this is likely to determine the nature of optimal

niches and thus the requirement for HIF function. If these hypotheses are shown to be correct, it would also suggest that HIF requirement will not only vary between patients, but also within a patient at different stages of the disease. Thus, the data from Valasco-Hernandez et al should give pause for more thought and an opportunity to probe more deeply into the interaction between hypoxic adaption and function of cell populations that initiate and propagate AML and other cancers. Conflict-of-interest disclosure: The author declares no competing financial interests. n REFERENCES 1. Velasco-Hernandez T, Hyrenius-Wittsten A, Rehn M, Bryder D, Cammenga J. HIF-1a can act as a tumor suppressor gene in murine acute myeloid leukemia. Blood. 2014;124(24): 3597-3607. 2. Suda T, Takubo K, Semenza GL. Metabolic regulation of hematopoietic stem cells in the hypoxic niche. Cell Stem Cell. 2011;9(4):298-310.

3. Kusumbe AP, Ramasamy SK, Adams RH. Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature. 2014;507(7492):323-328. 4. Arai F, Hirao A, Ohmura M, et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell. 2004;118(2):149-161. 5. Ishikawa F, Yoshida S, Saito Y, et al. Chemotherapyresistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat Biotechnol. 2007;25(11):1315-1321. 6. Takubo K, Goda N, Yamada W, et al. Regulation of the HIF-1alpha level is essential for hematopoietic stem cells. Cell Stem Cell. 2010;7(3):391-402. 7. Guitart AV, Subramani C, Armesilla-Diaz A, et al. Hif-2a is not essential for cell-autonomous hematopoietic stem cell maintenance. Blood. 2013;122(10):1741-1745. 8. Wang Y, Liu Y, Malek SN, Zheng P, Liu Y. Targeting HIF1a eliminates cancer stem cells in hematological malignancies. Cell Stem Cell. 2011;8(4):399-411. 9. Zhang H, Li H, Xi HS, Li S. HIF1a is required for survival maintenance of chronic myeloid leukemia stem cells. Blood. 2012;119(11):2595-2607. 10. Rouault-Pierre K, Lopez-Onieva L, Foster K, et al. HIF2a protects human hematopoietic stem/progenitors and acute myeloid leukemic cells from apoptosis induced by endoplasmic reticulum stress. Cell Stem Cell. 2013;13(5):549-563. © 2014 by The American Society of Hematology


Comment on Iqbal et al, page 3646

New checkpoint of the coagulant phenotype ----------------------------------------------------------------------------------------------------Janusz Rak


In this issue of Blood, Iqbal et al shed new light on how the procoagulant potential of monocytes/macrophages is controlled by the hitherto unsuspected mechanism modulating the fate of tissue factor (TF) messenger (m)RNA.1


onocytes, macrophages, and their precursors are cellular mavericks programmed to travel in blood and across tissue barriers to sites of infection, inflammation, injury, and repair.2 This property requires a precise, timely, and localized expression of different functional aptitudes. A startling example of this is the ability of monocytes to enter the circulating blood while effectively “managing” their relationship with the coagulation system.2 Contact with blood can be risky. Monocytes possess the intrinsic potential to activate clotting through expression of TF, the cell surface receptor for the coagulation factor (F)VII/VIIa and potent trigger of the


coagulation cascade.3 If monocytes were to express active TF in an unscheduled or exuberant manner, the consequences could be catastrophic, resulting in uncontrolled intravascular activation of clotting processes, as observed in sepsis.4 The remarkable feature of the hemostatic system is its ability to maintain the systemic liquidity of the circulating blood while being able to locally “solidify” blood components to plug up the site of a vascular injury by clots composed of fibrin and platelets. This is accomplished, in part, by the physical separation of latent clotting factors (zymogens) and their potential activators, such as procoagulant surfaces of extracellular matrix and TF expressed by cells outside of the


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2014 124: 3510-3511 doi:10.1182/blood-2014-10-605055

Targeting HIF function: the debate continues Paresh Vyas

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