Sex differences in the incidence of chronic myeloid leukemia

The incidence of chronic myeloid leukemia (CML), which is caused by BCR/ABL chimeric oncogene formation in a pluripotent hematopoietic stem cell (HSC), increases with age and exposure to ionizing radiation. CML is a comparatively well-characterized neoplasm, important for its own sake and useful for insights into other neoplasms. Here, Surveillance, Epidemiology and End Results (SEER) CML data are analyzed after considering possible misclassification of chronic myelo-monocytic leukemia as CML. For people older than 25 years, plots of male and female CML log incidences versus age at diagnosis are approximately parallel straight lines with males either above or to the left of females. This is consistent with males having a higher risk of developing CML or a shorter latency from initiation to diagnosis of CML. These distinct mechanisms cannot be distinguished using SEER data alone. Therefore, CML risks among male and female Japanese A-bomb survivors are also analyzed. The present analyses suggest that sex differences in CML incidence more likely result from differences in risk than in latency. The simplest but not the sole interpretation of this is that males have more target cells at risk to develop CML. Comprehensive mathematical models of CML could lead to a better understanding of the role of HSCs in CML and other preleukemias that can progress to acute leukemia.     

Global dynamics of hematopoietic stem cells and differentiated cells in a chronic myeloid leukemia model

We consider a mathematical model describing evolution of normal and leukemic hematopoietic stem cells (HSC) and differentiated cells in bone marrow. We focus on chronic myeloid leukemia (CML), a cancer of blood cells resulting from a malignant transformation of hematopoietic stem cells. The dynamics are given by a system of ordinary differential equations for normal and leukemic cells. Homeostasis regulates the proliferation of normal HSC and leads the dynamics to an equilibrium. This mechanism is partially efficient for leukemic cells. We define homeostasis by a functional of either hematopoietic stem cells, differentiated cells or both cell lines. We determine the number of hematopoietic stem cells and differentiated cells at equilibrium. Conditions for regeneration of hematopoiesis and persistence of CML are obtained from the global asymptotic stability of equilibrium states. We prove that normal and leukemic cells can not coexist for a long time. Numerical simulations illustrate our analytical results. The study may be helpful in understanding the dynamics of normal and leukemic hematopoietic cells.     

A mathematical model of hematopoiesis--I. Periodic chronic myelogenous leukemia

Periodic chronic myelogenous leukemia (PCML) is an interesting dynamical disease of the hematopoietic system in which oscillating levels of circulating leukocytes, platelets and/or reticulocytes are observed. Typically all of these three differentiated cell types have the same oscillation period, but the relation of the oscillation mean and amplitude to the normal levels is variable. Given the appearance of the abnormal Philadelphia chromosome in all of the nucleated progeny of the hematopoietic stem cells (HSCs), the most parsimonious conclusion is that chronic myelogenous leukemia, and its periodic variant, arise from derangements partially involving the dynamics of the stem cells. Here, we have synthesized several previous mathematical models of HSC dynamics, and models for the regulation of neutrophils, platelets and erythrocytes into a comprehensive model for the regulation of the hematopoietic system. Based on estimates of parameters for a typical normal human, we have systematically explored the changes in some of these parameters necessary to account for the quantitative data on leukocyte, platelet and reticulocyte cycling in 11 patients with PCML. Our results indicate that the critical model parameter changes required to simulate the PCML patient data are an increase in the amplification in the leukocyte line, an increase in the differentiation rate from the stem cell compartment into the leukocyte line, and the rate of apoptosis in the stem cell compartment. Our model system is particularly sensitive to changes in stem cell apoptosis rates, suggesting that changes in the numbers of proliferating stem cells may be important in generating PCML.     

Stability Analysis of a Model of Interaction Between the Immune System and Cancer Cells in Chronic Myelogenous Leukemia

We describe here a simple model for the interaction between leukemic cells and the autologous immune response in chronic phase chronic myelogenous leukemia (CML). This model is a simplified version of the model we proposed in Clapp et al. (Cancer Res 75:4053–4062, 2015). Our simplification is based on the observation that certain key characteristics of the dynamics of CML can be captured with a three-compartment model: two for the leukemic cells (stem cells and mature cells) and one for the immune response. We characterize the existence of steady states and their stability for generic forms of immunosuppressive effects of leukemic cells. We provide a complete co-dimension one bifurcation analysis. Our results show how clinical response to tyrosine kinase inhibitors treatment is compatible with the existence of a stable low disease, treatment-free steady state.     

Changes in the proteome associated with the action of Bcr-Abl tyrosine kinase are not related to transcriptional regulation

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disease, the hallmark of which is the Bcr-Abl protein tyrosine kinase (PTK). Without intervention the disease progresses from a benign chronic phase to a rapidly fatal blast crisis. To identify the molecular mechanisms underlying disease progression we used two-dimensional gel electrophoresis on a model we have previously described using the expression of a conditional mutant of Bcr-Abl PTK in a multipotent stem cell line, FDCP-Mix. Long term exposure of FDCP-Mix cells to Bcr-Abl mimics disease progression in CML. Four major differences were observed as a consequence of long term exposure to the Bcr-Abl PTK compared with cells exposed short term. The proteins were identified using matrix-assisted laser desorption ionization-time of flight mass spectrometry-generated peptide mass fingerprint data and liquid chromatography-tandem mass spectrometry-generated sequence information. Leukotriene A4 hydrolase, an enzyme known to be deregulated in CML, was found to be up-regulated. Annexin VI, vacuolar ATP synthase catalytic subunit A, and mortalin were found to be down-regulated. Poly(A) PCR cDNA analysis showed there was no correlation between the protein expression changes and mRNA levels. Western blot analysis also indicated no change in the levels of mortalin or leukotriene A4 hydrolase, indicating that post-translational events may modify protein content of the specific spots. Leukotriene B4 levels (product of leukotriene A4 hydrolase) were, however, reduced in cells exposed long term to Bcr-Abl activity. This study demonstrates the potential of proteomic analysis to define novel effects of oncogenes.     

Requirement for CD44 in homing and engraftment of BCR-ABL-expressing leukemic stem cells

In individuals with chronic myeloid leukemia (CML) treated by autologous hematopoietic stem cell (HSC) transplantation, malignant progenitors in the graft contribute to leukemic relapse, but the mechanisms of homing and engraftment of leukemic CML stem cells are unknown. Here we show that CD44 expression is increased on mouse stem-progenitor cells expressing BCR-ABL and that CD44 contributes functional E-selectin ligands. In a mouse retroviral transplantation model of CML, BCR-ABL1-transduced progenitors from CD44-mutant donors are defective in homing to recipient marrow, resulting in decreased engraftment and impaired induction of CML-like myeloproliferative disease. By contrast, CD44-deficient stem cells transduced with empty retrovirus engraft as efficiently as do wild-type HSCs. CD44 is dispensable for induction of acute B-lymphoblastic leukemia by BCR-ABL, indicating that CD44 is specifically required on leukemic cells that initiate CML. The requirement for donor CD44 is bypassed by direct intrafemoral injection of BCR-ABL1-transduced CD44-deficient stem cells or by coexpression of human CD44. Antibody to CD44 attenuates induction of CML-like leukemia in recipients. These results show that BCR-ABL-expressing leukemic stem cells depend to a greater extent on CD44 for homing and engraftment than do normal HSCs, and argue that CD44 blockade may be beneficial in autologous transplantation in CML.     

Impact of carnivory on human development and evolution revealed by a new unifying model of weaning in mammals

Our large brain, long life span and high fertility are key elements of human evolutionary success and are often thought to have evolved in interplay with tool use, carnivory and hunting. However, the specific impact of carnivory on human evolution, life history and development remains controversial. Here we show in quantitative terms that dietary profile is a key factor influencing time to weaning across a wide taxonomic range of mammals, including humans. In a model encompassing a total of 67 species and genera from 12 mammalian orders, adult brain mass and two dichotomous variables reflecting species differences regarding limb biomechanics and dietary profile, accounted for 75.5%, 10.3% and 3.4% of variance in time to weaning, respectively, together capturing 89.2% of total variance. Crucially, carnivory predicted the time point of early weaning in humans with remarkable precision, yielding a prediction error of less than 5% with a sample of forty-six human natural fertility societies as reference. Hence, carnivory appears to provide both a necessary and sufficient explanation as to why humans wean so much earlier than the great apes. While early weaning is regarded as essentially differentiating the genus Homo from the great apes, its timing seems to be determined by the same limited set of factors in humans as in mammals in general, despite some 90 million years of evolution. Our analysis emphasizes the high degree of similarity of relative time scales in mammalian development and life history across 67 genera from 12 mammalian orders and shows that the impact of carnivory on time to weaning in humans is quantifiable, and critical. Since early weaning yields shorter interbirth intervals and higher rates of reproduction, with profound effects on population dynamics, our findings highlight the emergence of carnivory as a process fundamentally determining human evolution.     

Regulation of hematopoietic stem cells in the niche

Hematopoiesis provides a suitable model for understanding adult stem cells and their niche. Hematopoietic stem cells(HSCs) continuously produce blood cells through orchestrated proliferation, self-renewal, and differentiation in the bone marrow(BM). Within the BM exists a highly organized microenvironment termed "niche" where stem cells reside and are maintained. HSC niche is the first evidence that a microenvironment contributes to protecting stem cell integrity and functionality in mammals. Although multiple models exist, recent progress has principally elucidated the cellular complexity of the HSC niche that maintains and regulates HSCs in BM. Here we introduce the development and summarize the achievements of HSC niche studies.     

Genetic and pharmacologic inhibition of β-catenin targets imatinib-resistant leukemia stem cells in CML

A key characteristic of hematopoietic stem cells (HSCs) is the ability to self-renew. Genetic deletion of β-catenin during fetal HSC development leads to impairment of self-renewal while β-catenin is dispensable in fully developed adult HSCs. Whether β-catenin is required for maintenance of fully developed CML leukemia stem cells (LSCs) is unknown. Here, we use a conditional mouse model to show that deletion of β-catenin after CML initiation does not lead to a significant increase in survival. However, deletion of β-catenin synergizes with imatinib (IM) to delay disease recurrence after imatinib discontinuation and to abrogate CML stem cells. These effects can be mimicked by pharmacologic inhibition of β-catenin via modulation of prostaglandin signaling. Treatment with the cyclooxygenase inhibitor indomethacin reduces β-catenin levels and leads to a reduction in LSCs. In conclusion, inhibiting β-catenin by genetic inactivation or pharmacologic modulation is an effective combination therapy with imatinib and targets CML stem cells.     

Targeted therapies and autophagy: new insights from chronic myeloid leukemia

Patients who develop chronic myeloid leukemia (CML) are currently treated with tyrosine kinase inhibitors (TKIs), which inhibit the function of the oncogene BCR/Abl. Most CML cells undergo apoptosis when BCR/Abl tyrosine kinase activity is suppressed by TKIs. Cells surviving drug treatment are either stem cells (CML in early phase) or cells with BCR/Abl-dependent or -independent mechanisms of drug resistance (CML in advanced phase). Since survival of these cells is thought to be responsible for disease recurrence, it is critical to find ways to fully eradicate CML stem cells. We have recently shown that when CML cells, including stem cells, are exposed to TKI they activate an autophagic program, which relies on intracellular calcium and is not inhibited by Bcl-2. Pharmacological or RNAi-mediated inhibition of autophagy potentiates the effect of TKI in inducing death of CML cells, including the stem cells. These data strongly suggest that inhibition of autophagy may improve the therapeutic effects of TKIs in the treatment of CML. In addition, they give credence to the idea that in cancer cells autophagy is part of a stereotypic response to stress and specifically to abrogation of their main oncogenic signal(s).     

Carboxyamidotriazole-orotate inhibits the growth of imatinib-resistant chronic myeloid leukaemia cells and modulates exosomes-stimulated angiogenesis

The Bcr/Abl kinase has been targeted for the treatment of chronic myelogenous leukaemia (CML) by imatinib mesylate. While imatinib has been extremely effective for chronic phase CML, blast crisis CML are often resistant. New therapeutic options are therefore needed for this fatal disease. Although more common in solid tumors, increased microvessel density was also reported in chronic myelogenous leukaemia and was associated with a significant increase of angiogenic factors, suggesting that vascularity in hematologic malignancies is a controlled process and may play a role in the leukaemogenic process thus representing an alternative therapeutic target. Carboxyamidotriazole-orotate (CTO) is the orotate salt form of carboxyamidotriazole (CAI), an orally bioavailable signal transduction inhibitor that in vitro has been shown to possess antileukaemic activities. CTO, which has a reduced toxicity, increased oral bioavailability and stronger efficacy when compared to the parental compound, was tested in this study for its ability to affect imatinib-resistant CML tumor growth in a xenograft model. The active cross talk between endothelial cells and leukemic cells in the bone marrow involving exosomes plays an important role in modulating the process of neovascularization in CML. We have thus investigated the effects of CTO on exosome-stimulated angiogenesis. Our results indicate that CTO may be effective in targeting both cancer cell growth and the tumor microenvironment, thus suggesting a potential therapeutic utility for CTO in leukaemia patients.     

The risk of chronic myeloid leukemia: can the dose-response curve be U-shaped?

Chronic myeloid leukemia (CML) is caused by a BCR-ABL chromosome translocation in a primitive hematopoietic stem cell. The number of hematopoietic stem cells in the body is thus a major factor in CML risk. Evidence suggests that the number of hematopoietic stem cells in the body is only loosely regulated, having a broad "dead-band" of physiologically acceptable values. The existence of a dead-band is important, because it would imply that low levels of hematopoietic stem cell killing can be permanent; i.e., it would imply that low doses of ionizing radiation can cause permanent reductions in the total number of CML target cells and thus permanent reductions in the subsequent risk of spontaneous CML. Such reductions in risk could be substantial if hematopoietic stem cells are also hypersensitive to radiation killing at low dose. Our calculations indicate that, due to dead-band hematopoietic stem cell control, if hematopoietic stem cells are as hypersensitive to killing at low doses as epithelial cells, reductions in the spontaneous CML risk could exceed the low-dose risks of induced CML; i.e., the net lifetime CML risk could have a U-shaped dose-response curve.     

TGF-beta1-induced PI3K/Akt/NF-kappaB/MMP9 signalling pathway is activated in Philadelphia chromosome-positive chronic myeloid leukaemia hemangioblasts

Overwhelming evidence from chronic myeloid leukaemia (CML) research indicates that patients harbour quiescent CML stem cells that are responsible for blast crisis. While the haematopoietic stem cell (HSC) origin of CML was first suggested over 30 years ago, recently CML-initiating cells beyond HSCs are also being investigated. We have previously isolated fetal liver kinase-1-positive (Flk1(+)) cells carrying the BCR/ABL fusion gene from the bone marrow of Philadelphia chromosome-positive (Ph(+)) patients with hemangioblast property. Here, we show that these cells behave abnormally comparing with the hemangioblasts in healthy donors. These Ph(+) putative CML hemangioblast up-regulated TGF-β1 and result in activating matrix metalloproteinase-9 to enhance s-KitL and s-ICAM-1 secretion. Further studies showed that phosphatidylinositol-3 kinase (PI3K)/Akt/nuclear factor-κB signalling pathway was involved in CML pathogenesis. These findings provide direct evidence for the first time that hemangioblasts beyond HSCs play a critical role in the progression of CML.     

An overview of chronic myeloid leukemia and its animal models

Chronic myeloid leukemia(CML) is a form of leukemia characterized by the presence of clonal bone marrow stem cells with the proliferation of mature granulocytes(neutrophils, eosinophils, and basophils) and their precursors. CML is a type of myeloproliferative disease associated with a characteristic chromosomal translocation called the Philadelphia(Ph) chromosome or t(9;22) translocation(BCR-ABL). CML is now usually treated with targeted drugs called tyrosine kinase inhibitors(TKIs). The mechanism and natural history of CML is still unclear. Here, we summarize the present CML animal disease models and compare them with each other. Meanwhile, we propose that it is a very wise choice to establish zebrafish(Danio rerio) CML model mimics clinical CML. This model could be used to learn more about the mechanism of CML, and to aid in the development of new drugs to treat CML.     

Targeting tetramer-forming GABPβ isoforms impairs self-renewal of hematopoietic and leukemic stem cells

Hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs) are both capable of self-renewal, with HSCs sustaining multiple blood lineage differentiation and LSCs indefinitely propagating leukemia. The GABP complex, consisting of DNA binding GABPα subunit and transactivation GABPβ subunit, critically regulates HSC multipotency and self-renewal via controlling an essential gene regulatory module. Two GABPβ isoforms, GABPβ1L and GABPβ2, contribute to assembly of GABPα(2)β(2) tetramer. We demonstrate that GABPβ1L/β2 deficiency specifically impairs HSC quiescence and survival, with little impact on cell cycle or apoptosis in differentiated blood cells. The HSC-specific effect is mechanistically ascribed to perturbed integrity of the GABP-controlled gene regulatory module in HSCs. Targeting GABPβ1L/β2 also impairs LSC self-renewal in p210(BCR-ABL)-induced chronic myelogenous leukemia (CML) and exhibits synergistic effects with tyrosine kinase inhibitor imatinib therapy in inhibiting CML propagation. These findings identify the tetramer-forming GABPβ isoforms as specific HSC regulators and potential therapeutic targets in treating LSC-based hematological malignancy.     

Telomere dynamics in hematopoietic stem cells

The hematopoietic system has an outstanding regenerative capacity which depends on a relatively small population of hematopoietic stem cells (HSC). In contrast to normal human cells, blood-forming stem cells, like most of their counterparts from other adult tissues, exhibit telomerase activity to a certain level. Nevertheless, this telomerase activity does not prevent telomere shortening in HSC, suggesting a restriction of their proliferative capacity. Here, we review recent studies on telomere dynamics in HSC of humans and mice. Furthermore, we discuss the impact of telomere manipulation in HSC for possible clinical applications and speculate on functions of telomerase beyond telomere lengthening.     

The dimeric Mcm8–9 complex of Xenopus laevis likely has a conserved function for resistance to DNA damage

The success of Imatinib mesylate (STI571, Gleevec) in treating chronic myeloid leukemia (CML) is, to date, the crowning achievement of targeted molecular therapy in cancer. Nearly 90% of newly diagnosed patients treated with Imatinib in the chronic phase of the disease achieve a complete cytogenetic response. However, more than 95% of these patients retain detectable levels of BCR-ABL mRNA and patients discontinuing Imatinib therapy almost invariably relapse, demonstrating that an Imatinib insensitive population of leukemia-initiating cells (LICs) persists in nearly all patients. These findings underscore the need for treatments specifically targeting the leukemia-initiating population of CML cells. While mounting evidence suggests that the LIC in the chronic phase of CML is the BCR-ABL positive hematopoietic stem cell, several recent publications suggest that during CML blast crisis, a granulocyte-macrophage progenitor (GMP) population also acquires LIC properties through activation of the β-catenin pathway. Characterization of these cells and evaluation of their sensitivity to Imatinib is critical to our understanding and treatment of CML blast crisis.     

Cross-species transmission of CWD prions

Prions cause fatal neurodegenerative diseases in humans and animals and can be transmitted zoonotically. Chronic wasting disease (CWD) is a highly transmissible prion disease of wild deer and elk that affects cervids over extensive regions of the United States and Canada. The risk of cross-species CWD transmission has been experimentally evaluated in a wide array of mammals, including non-human primates and mouse models expressing human cellular prion protein. Here we review the determinants of cross-species CWD transmission, and propose a model that may explain a structural barrier for CWD transmission to humans.     

Targeted disruption of the Artemis murine counterpart results in SCID and defective V(D)J recombination that is partially corrected with bone marrow transplantation

Artemis is a mammalian protein, the absence of which results in SCID in Athabascan-speaking Native Americans (SCIDA). This novel protein has been implicated in DNA double-strand break repair and V(D)J recombination. We have cloned the Artemis murine counterpart, mArt, and generated a mouse with a targeted disruption of mArt. Artemis-deficient mice show a similar T-B- NK+ immunodeficiency phenotype, and carry a profound impairment in coding joint rearrangement, while retaining intact signal ends and close to normal signal joint formation. mArt-/- embryonic fibroblasts show increased sensitivity to ionizing radiation. Hemopoietic stem cell (HSC) transplantation using 500-5000 enriched congenic, but not allogeneic mismatched HSC corrected the T cell and partially corrected the B cell defect. Large numbers (40,000) of allogeneic mismatched HSC or pretreatment with 300 cGy of radiation overcame graft resistance, resulting in limited B cell engraftment. Our results suggest that the V(D)J and DNA repair defects seen in this mArt-/- mouse model are comparable to those in humans with Artemis deficiency, and that the recovery of immunity following HSC transplantation favors T rather than B cell reconstitution, consistent with what is seen in children with this form of SCID.