Since the discovery of leukemic stem cells (LSCs) over a decade ago, many of their critical biological properties have been elucidated, including their distinct replicative properties, cell surface ...phenotypes, their increased resistance to chemotherapeutic drugs and the involvement of growth-promoting chromosomal translocations. Of particular importance is their ability to transfer malignancy to non-obese diabetic-severe combined immunodeficient (NOD-SCID) mice. Furthermore, numerous studies demonstrate that acute myeloid leukemia arises from mutations at the level of stem cell, and chronic myeloid leukemia is also a stem cell disease. In this review, we will evaluate the main characteristics of LSCs elucidated in several well-documented leukemias. In addition, we will discuss points of therapeutic intervention. Promising therapeutic approaches include the targeting of key signal transduction pathways (for example, PI3K, Rac and Wnt) with small-molecule inhibitors and specific cell surface molecules (for example, CD33, CD44 and CD123), with effective cytotoxic antibodies. Also, statins, which are already widely therapeutically used for a variety of diseases, show potential in targeting LSCs. In addition, drugs that inhibit ATP-binding cassette transporter proteins are being extensively studied, as they are important in drug resistance-a frequent characteristic of LSCs. Although the specific targeting of LSCs is a relatively new field, it is a highly promising battleground that may reveal the Holy Grail of cancer therapy.
Mutations and chromosomal translocations occur in leukemic cells that result in elevated expression or constitutive activation of various growth factor receptors and downstream kinases. The ...Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways are often activated by mutations in upstream genes. The Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways are regulated by upstream Ras that is frequently mutated in human cancer. Recently, it has been observed that the FLT-3 and Jak kinases and the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) phosphatase are also frequently mutated or their expression is altered in certain hematopoietic neoplasms. Many of the events elicited by the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways have direct effects on survival pathways. Aberrant regulation of the survival pathways can contribute to uncontrolled cell growth and lead to leukemia. In this review, we describe the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT signaling cascades and summarize recent data regarding the regulation and mutation status of these pathways and their involvement in leukemia.
Glycogen synthase kinase-3 (GSK-3) is well documented to participate in a complex array of critical cellular processes. It was initially identified in rat skeletal muscle as a serine/threonine kinase ...that phosphorylated and inactivated glycogen synthase. This versatile protein is involved in numerous signaling pathways that influence metabolism, embryogenesis, differentiation, migration, cell cycle progression and survival. Recently, GSK-3 has been implicated in leukemia stem cell pathophysiology and may be an appropriate target for its eradication. In this review, we will discuss the roles that GSK-3 plays in hematopoiesis and leukemogenesis as how this pivotal kinase can interact with multiple signaling pathways such as: Wnt/β-catenin, phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/Akt/mammalian target of rapamycin (mTOR), Ras/Raf/MEK/extracellular signal-regulated kinase (ERK), Notch and others. Moreover, we will discuss how targeting GSK-3 and these other pathways can improve leukemia therapy and may overcome therapeutic resistance. In summary, GSK-3 is a crucial regulatory kinase interacting with multiple pathways to control various physiological processes, as well as leukemia stem cells, leukemia progression and therapeutic resistance. GSK-3 and Wnt are clearly intriguing therapeutic targets.
The roles of the JAK/STAT, Raf/MEK/ERK and PI3K/Akt signal transduction pathways and the BCR-ABL oncoprotein in leukemogenesis and their importance in the regulation of cell cycle progression and ...apoptosis are discussed in this review. These pathways have evolved regulatory proteins, which serve to limit their proliferative and antiapoptotic effects. Small molecular weight cell membrane-permeable drugs that target these pathways have been developed for leukemia therapy. One such example is imatinib mesylate, which targets the BCR-ABL kinase as well as a few structurally related kinases. This drug has proven to be effective in the treatment of CML patients. However, leukemic cells have evolved mechanisms to become resistant to this drug. A means to combat drug resistance is to target other prominent signaling components involved in the pathway or to inhibit BCR-ABL by other mechanisms. Treatment of imatinib-resistant leukemia cells with drugs that target Ras (farnysyl transferase inhibitors) or with the protein destabilizer geldanamycin has proven to be a means to inhibit the growth of resistant cells. This review will tie together three important signal transduction pathways involved in the regulation of hematopoietic cell growth and indicate how their expression is dysregulated by the BCR-ABL oncoprotein.
The Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways are frequently activated in leukemia and other hematopoietic disorders by upstream mutations in cytokine receptors, aberrant chromosomal ...translocations as well as other genetic mechanisms. The Jak2 kinase is frequently mutated in many myeloproliferative disorders. Effective targeting of these pathways may result in suppression of cell growth and death of leukemic cells. Furthermore it may be possible to combine various chemotherapeutic and antibody-based therapies with low molecular weight, cell membrane-permeable inhibitors which target the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to ultimately suppress the survival pathways, induce apoptosis and inhibit leukemic growth. In this review, we summarize how suppression of these pathways may inhibit key survival networks important in leukemogenesis and leukemia therapy as well as the treatment of other hematopoietic disorders. Targeting of these and additional cascades may also improve the therapy of chronic myelogenous leukemia, which are resistant to BCR-ABL inhibitors. Furthermore, we discuss how targeting of the leukemia microenvironment and the leukemia stem cell are emerging fields and challenges in targeted therapies.
Mantle-cell lymphoma (MCL) is a rather aggressive B-cell malignancy whose considerable variability of individual outcome is associated with clinical characteristics (Mantle Cell Lymphoma ...International Prognostic Index MIPI). The Ki-67 index is a strong independent prognostic factor; however, the biologic MIPI (MIPI-b) distinguishes only two groups, which does not appropriately depict the clinical heterogeneity. By using the cohort from the European MCL Younger and MCL Elderly trials, we aimed to evaluate the additional prognostic impact of cytology and growth pattern and to improve risk stratification with the Ki-67 index and MIPI.
Diagnostic tumor biopsies were reviewed by the European Mantle Cell Lymphoma Pathology Panel to determine Ki-67 index by using published guidelines, cytology, and growth pattern. We evaluated prognostic effects for overall survival (OS) by Cox regression. For the cohort used for MIPI-b development (German Low-Grade Lymphoma Study Group GLSG 1996 and GLSG2000), we checked whether the equally weighted combination of Ki-67 index (dichotomized at the validated 30% cutoff) and MIPI risk groups was adequate and compared the prognostic power of this modified combination to MIPI and MIPI-b for the MCL Younger/MCL Elderly cohort.
The Ki-67 index was assessed in 508 of 832 patients (median age, 62 years). Blastoid cytology was associated with inferior OS independently of MIPI but not independently of the Ki-67 index. Growth pattern was not independently prognostic. The modified combination of the Ki-67 index and MIPI separated four groups with 5-year OS: 85%, 72%, 43%, and 17% (P < .001) and was more discriminative than MIPI and MIPI-b.
Using the Ki-67 index is superior to using cytology and growth pattern as prognostic factors in MCL. The modified combination of the Ki-67 index and MIPI showed a refined risk stratification, reflecting their strong complementary prognostic effects while integrating the most relevant prognostic factors available in clinical routine.
P-type point contact (PPC) HPGe detectors are a leading technology for rare event searches due to their excellent energy resolution, low thresholds, and multi-site event rejection capabilities. We ...have characterized a PPC detector’s response to
α
particles incident on the sensitive passivated and p
+
surfaces, a previously poorly-understood source of background. The detector studied is identical to those in the
Majorana
Demonstrator
experiment, a search for neutrinoless double-beta decay (
0
ν
β
β
) in
76
Ge.
α
decays on most of the passivated surface exhibit significant energy loss due to charge trapping, with waveforms exhibiting a delayed charge recovery (DCR) signature caused by the slow collection of a fraction of the trapped charge. The DCR is found to be complementary to existing methods of
α
identification, reliably identifying
α
background events on the passivated surface of the detector. We demonstrate effective rejection of all surface
α
events (to within statistical uncertainty) with a loss of only 0.2% of bulk events by combining the DCR discriminator with previously-used methods. The DCR discriminator has been used to reduce the background rate in the
0
ν
β
β
region of interest window by an order of magnitude in the
Majorana
Demonstrator
and will be used in the upcoming LEGEND-200 experiment.
PDF
