The Quantal Theory of Immunity

The following sections are included:

• Acknowledgements

• Prologue

• Contents

The immune system has fascinated scientists ever since Sir Edward Jenner demonstrated the quantal (all-or-none) nature of protection against smallpox in 1798, over 200 years ago. Although it had been known for centuries that some diseases never strike twice, smallpox among them, Jenner demonstrated for the first time that one could achieve such protection artificially and safely by exposure to an avirulent form of the disease, a practice that came to be known as vaccination (from the Latin vaccinus, from cows).¹ Working meticulously in his medical practice in the English countryside, Jenner tested the well-known observation that milkmaids were immune to smallpox; provided they had previously contracted a self-limited pox disease from the udders of cows. Thus, Jenner showed that immunity to smallpox could be transferred to individuals who had never been exposed to either cowpox or smallpox by inoculating them with pus from milkmaids who had cowpox…

Using monoclonal T cells, it was possible to create a rapid unambiguous in vitro bioassay for the mitogenic activity in the lymphocyte-conditioned media, termed T cell growth factor (TCGF), and to then identify its molecular characteristics.¹ Lymphocyte-conditioned media was found to contain a single 15 kDa glycoprotein that was responsible for long-term T cell growth.² Moreover, using the bioassay, enough TCGF protein could be purified to generate MoAbs that could be used as immunoaffinity reagents to purify large amounts (i.e. milligrams) of homogeneous protein in a single step.³ In addition, biosynthetically radiolabeled TCGF was purified and used to demonstrate the first cytokine receptor, which had all of the characteristics of a classic hormone receptor including high affinity, ligand specificity, target cell specificity and saturation binding.⁴ Moreover, the TCGF radioreceptor assay was used to identify the first MoAb reactive with a cytokine receptor.⁵…

Burnet correctly based the behavior of the immune system on decisions made by individual cells comprising the system, and also correctly predicted that each cell reacts with an environmental antigen via a clone-specific cell surface receptor. However, Burnet had no way of knowing how the antigen receptor molecules actually "recognize" a foreign antigen molecule, and what molecules are involved in transferring the information imparted by antigen-receptor interaction at the cell surface to the cellular interior. Moreover, how this information becomes translated into determining the tempo, magnitude and duration of a systemic immune response simply could not be discerned in 1959 because the molecules involved had not yet been discovered…

Any new theory that attempts to explain how the immune system functions to discriminate between non-self foreign antigens versus self auto-antigens must first obey Burnet's Law of Clonal Selection and expansion at the level of each individual cell. In addition, any new theory must provide a molecular explanation for the behavior of the individual cells comprising the system. Most importantly, the theory must account for the reactivity of the whole immune system to an antigen, whether non-self or self. This should be possible, now that we know the molecular nature of the receptors for antigens as well as the molecular nature of antigens. In addition, we have identified the leukocytotrophic hormone molecules as well as their receptor molecules which take over the control of immune reactivity after the introduction of an antigen…

Before focusing on the critical molecules responsible for lymphocyte activation and proliferation, it is helpful to understand the evolution of our knowledge of the regulation of the proliferation of all somatic cells. Beginning in 1932 with studies on bacterial cell growth, numerous experiments with many different cell types over the following 50 years revealed that the cell cycle times of individual cells within a population follow a normal distribution when examined as a function of the division rate (termed the rate-normal distribution) (reviewed in Ref. 1). Thus, some cells have very rapid generation times, while others are slower, with the majority of cells within the population distributed about the mean. This distribution is also a log-normal distribution, since rate is a reciprocal of the time required to progress through the cell cycle. Data from experiments with the flagellated protozoan Euglena gracilis, often quoted in the cell cycle literature, are illustrated in Fig. 5.1 to emphasize the variability in the rate of growth of individual cells within a population.²…

To understand how the extremely complex immune system generates a quantal decision as to whether there is immunity to an antigen, reductionism is the only possible experimental approach. In order to apply reductionism to this situation, it is helpful to begin with the end result. This means studying lymphocytes after they have already undergone a proliferative clonal expansion having received the molecular signals initiated by an antigen that result in expression of the mitogenic cytokines and their receptors, as well as the result of the cytokine/receptor interaction, which results in the activation of signaling molecules, TFs and genetic programs that actually drive cell cycle progression and subsequent differentiation to effector function. In this discussion, one premise is that the same principles found to govern the IL-2/IL-2R interaction govern the ligand/receptor interactions of all cytokine/receptor pairs. Moreover, even though the discussion to follow is focused on T cells, another premise is that the principles are similar for B cells and indeed for all cells that make up a metazoan organism, the only differences being the tissue/cell-specific cytokine/receptor pairs, and the signaling pathways, TFs and genes that they activate. Thus, we are discussing fundamental biological processes…

From quantitative IL-2/IL-2R equilibrium and kinetic binding experiments, it was found that there is a mean of ~1000 high affinity IL-2R sites/cell on normal human antigen-activated T cells that bind IL-2 with a very rapid association rate (κ = 1 × 10⁷ sec^-1M^-1) and a relatively slow dissociation rate (κ' = 1 × 10^-4 sec^-1).¹ Consequently, steady state binding of IL-2 occurs within 10–15 minutes. However, as already noted, synchronized T cells require several hours of IL-2 exposure to lead to the quantal decision to progress beyond the R-point, synthesize nucleotides and replicate DNA. Thus, occupancy of only 1000 IL-2R sites for 10 minutes does not lead to the intracellular changes necessary for G₁ progression. Just like serum-stimulated MEFs, if IL-2 is withdrawn before the R-point, the cell will not make the G₁-S-phase transition. For the first time the structures of the IL- 2 molecule and the IL-2R chain molecules could be examined to determine how the IL-2/IL-2R interaction occurs and initiates the signaling process in T cells, increasing our understanding of how this quantal decision is made. It must be noted from the start that to signal a quantal cellular proliferative response the molecular processes must be "hard-wired" so that the quantitative information of the number of IL-2/IL-2R interactions that occur at the cell surface is transferred to the cell interior, and ultimately to the nucleus…

The earliest experiments with IL-2-dependent cloned T cells revealed that as the cells proliferate the IL-2 concentration progressively declines, as shown in Fig. 8.1. Moreover, once IL-2 concentrations decline to low levels, IL-2-dependent cells rapidly undergo apoptosis. Therefore, it appeared that IL-2-dependent cells somehow consume IL-2 and that IL-2 is necessary not only for proliferation but also for survival. As soon as radiolabeled IL-2 was available, IL-2 was found to be degraded into a trichloroacetic acid (TCA) soluble form by IL-2-dependent cells, indicating that the cells metabolize the radiolabeled IL-2 molecules into smaller forms that could not be precipitated by TCA.¹…

When each of the three IL-2R chains were identified,^1–4 and their cDNAs cloned and sequenced,^5–8 it was surprising that the sequences of the cytoplasmic domains did not reveal any known enzymatic motifs capable of generating biochemical reactions in the cell interior. Even before the identification of the IL-2R chains, experiments had revealed very rapid IL-2/IL-2R-dependent phosphorylation of multiple cytoplasmic proteins.⁹ In addition, it had already been determined that the cytoplasmic domains of the epidermal growth factor receptor (EGFR) and the platelet-derived growth factor receptor (PDGFR) contained sequences consistent with PTK activity. These are now called receptor tyrosine kinases (RTK)…

In addition to Y510, JAK1 and JAK3 also phosphorylate Y338 on the IL-2R β chain, which serves as a docking site for the adapter protein, Shc.^1,2 Shc is ubiquitously expressed and exists in three isoforms of 66, 52, and 48 kDa.^3,4 The Shc protein is composed of three domains, an N-terminal domain that interacts with proteins containing pYs, a (gly/pro)-rich collagen homology domain, and an Src-homology-2 (SH2) domain, which binds to Y338 on the IL-2R β chain. Once recruited to the IL-2R β chain, Shc activates at least two downstream pathways, the PI3K (phosphoinositide 3-kinase) pathway, and the MAPK (mitogen activated protein kinase) pathway.⁴ Shc activates the PI3K pathway by recruiting the adapter protein Grb2, which in turn recruits the adapter protein Gab2, followed by the p85 PI3K regulatory subunit. Formation of the Shc/Grb2/Gab2/p85 complex ultimately leads to activation of the catalytic subunit of PI3K, p110, which converts phosphatidylinositol 4,5-bisphosphate into the lipid second messenger phosphatidylinositol 3,4,5-triphosphate (PIP₃) in the cell membrane. PIP₃ then recruits several mediators to the cell membrane, which are proteins containing pleckstrin homology (PH) domains, such as 3-phosphoinositide-dependent kinase-1 (PDK1), PKB (a.k.a. Akt), and the 70-kDa ribosomal S6 kinases (S6Ks). PKB regulates glucose uptake and protein synthesis by increasing the kinase activity of the mammalian Target of Rapamycin (mTOR)…

Once it is known that the number of triggered IL-2Rs determines quantal T cell DNA replication and cytokinesis, and thereby both the number of clones responding, as well as the extent of the clonal expansion (i.e. the systemic T cell immune response), the next critical molecular question is what determines the number of IL-2 molecules produced/cell and the number of IL-2Rs expressed by an antigen-activated T cell? Thus, working backward from IL-2 protein molecules to the IL-2 gene, and from the transcription factors and signaling pathways regulating IL-2 gene expression, we know that only antigen-activated T cells express IL-2 genes. After the antigen is cleared, there is no longer a positive drive on the system, and consequently immunologists have been comfortable with the notion that the regulation of the immune response is entirely antigen-dependent, despite the added complexity of the endogenous leukocytotophic hormonal system…

Given that three families of transcription factors must be activated in a coordinated and quantal fashion by the TCR complex, the question arises as to how this digital response on the part of the cell is created. Various theories have been proposed to account for the biophysics and biochemistry of TCR complex signaling, including induced allosteric changes in the TCR,¹ the duration of the pMHC/TCR complex interaction,² kinetic proofreading,³ and membrane segregation of signaling proteins (reviewed in Ref. 4). However, as detailed by Altan-Bonnet and co-workers, none of these theories explain the three characteristics of TCR activation, speed, sensitivity and specificity, which they have termed the S³ characteristics of TCR activation. Thus, theoretical models that explain TCR signaling must simultaneously account for the exquisite specificity of pMHC discrimination (i.e. agonist peptides versus non-agonist peptides), the high sensitivity of activation (i.e. only a few agonistic pMHC complexes trigger), and the speed of the biochemical response (i.e. calcium or ppERK elevations have been found to occur within seconds of TCR occupancy). The mechanoreceptor as described by the Reinherz group provides for a new notion of how the TCR itself may signal to the interior with both specificity and sensitivity, but we must now begin to discern how the signal is propagated via the cytoplasmic signaling pathways…

Once it was possible to quantify IL-2 concentrations via the bioassay, it was found that upon mitogenic activation, IL-2 could be first detected within six hours, gradually rising to a peak after 48 hours, followed by a more rapid decline to undetectable levels by 96 hours. As already discussed in Chap. 8, one of the explanations for the decline in detectable IL-2 is the cellular metabolism of IL-2 by IL-2R⁺ cells. However, IL-2 appeared to be different than other cytokines expressed upon TCR signaling, e.g. IFNγ, which rises to a plateau several hours after mitogenic activation and does not decline as the cells in culture proliferate. Early on, we hypothesized that perhaps there was a classic negative feedback regulation of IL-2 at play. We looked for a soluble negative regulator that could function to inhibit IL-2 activity in the bioassay, but could find no evidence for one. Even so, the notion that there must be a system to negatively regulate the IL-2-promoted proliferative expansion of antigen-activated T cell clones made biological (and endocrinological) sense, especially as it became obvious that the magnitude of the systemic immune response is controlled by the endogenous IL-2/IL-2R leukocytotrophic hormonal system,^1,2 instead of antigen per se. Actually, the existence of a leukocytotrophic hormonal system that regulates the immune response was first proposed by Sir Peter Medawar in 1973,³ and formally shown to exist by the discovery of the IL-2 molecule and IL-2Rs 10 years later.^4,5 However, one hallmark of an internally regulated hormonal system is negative feedback control, and this property of an endocrine system was lacking…

Given the pivotal role of the IL-2/IL-2R interaction in driving both the proliferative clonal expansion of antigen-selected T cells, as well as the negative feedback regulation of TCR-signaled IL-2 production, it follows that loss of such a high fidelity control of the systemic immune response will inevitably lead to immune system diseases. In particular, mutations in the genes encoding the critical molecules of the negative feedback loops should result in a lowering of the threshold of the discrimination of self versus non-self recognition, so that autoimmune diseases might ensue. Actually, we have already touched on the severe lethal autoimmune syndrome observed when the genes encoding CTLA-4 are deleted…

In 1949 a spontaneous mutation occurred in a mouse colony at Oak Ridge Tennessee.¹ The mutation was propagated and reported in 1959 to be X-linked and recessive, leading to a failure to thrive syndrome in males, manifested by ruffled fur and weight loss, hence the designation scurfy. More than 30 years later, in the early 1990s, the scurfy mouse was demonstrated to be suffering from an autoimmune lymphoproliferative syndrome very similar to that of the IL-2 (-/-) mouse and the CTLA-4 (-/-) mouse.^2,3 Remarkably, the syndrome is very acute with an onset soon after birth and a fully developed disease before maturity, leading to death by three weeks of age. Gross morphologic lesions of the scurfy syndrome include runting, scaly skin, squinted eyes, hepatosplenomegaly, and enlarged lymph nodes. The characteristic histological finding is a lymphohistiocytic proliferation and infiltration that effaces lymph node architecture, thickens the dermis, and forms nodular germinal center-like accumulations in the portal areas of the liver. Like the IL-2 (-/-) mouse, the scurfy males suffer from a severe autoimmune hemolytic anemia, and a marked polyclonal hypergammaglobulinemia. A factor of crucial importance, scurfy heterozygous females (i.e. X^sf/X⁺) are entirely normal, so that normal T cells appear to somehow "suppress" the T cells that carry the mutation from becoming hyperactive, in that the extra X chromosome in females should be randomly inactivated in early embryogenesis. Therefore, 50% of the T cells should contain the mutant gene, while 50% should contain a normal gene…

Early in the investigation of the role of the thymus in the immune system, in 1962 J.F.A.P. Miller showed that although thymectomy of adult mice leads to no discernible abnormalities, neonatal thymectomy within the first three days of life (d3Tx) results in dramatic pathology. For the first four weeks of life, d3Tx mice appear grossly normal and grow identically with sham-thymectomized control mice. However, thereafter the d3Tx mice fail to thrive and lose weight, becoming runted with the gross appearance of the IL-2 (-/-) mice, CTLA-4 (-/-) mice and scurfy mice, and die prematurely from a syndrome characterized by wasting and diarrhea.¹ It is also noteworthy that neonatal thymectomy results in mice that are lymphopenic, even though they appear grossly normal for the first few weeks of life. Moreover, they are immunocompromised, and are unable to mount an antibody response to immunization with Salmonella typhi or to reject allogeneic or even xenogeneic skin grafts. Accordingly, these d3Tx mice are definitely immunocompromised, so it was paradoxical that they should die from a wasting disease that resembles graft versus host disease (GvHd), with infiltration of many organs with activated lymphocytes, and Miller emphasized this point, in particular…

Because the IL-2Rα chain (CD25) is a specific marker for antigenactivated effector T cells, it was not immediately obvious how and why CD4⁺CD25⁺ T cells could prevent the activation of potential self-pMHC-reactive T cells in lymphopenic d3Tx mice. The internal environment in these lymphopenic animals, which have elevated concentrations of IL-7, is clearly abnormal, and the self-pMHC/ IL-7-driven expansion of self-reactive clones could very well contribute to the pathological attack on normal tissues observed in these mice. In this regard, it is worthy of mention that the only known regulators of IL-2Rα chain (CD25) expression are the TCR/CD3/CD28 activation of the Rel TFs and the IL-2-dependent activation of STAT5, with STAT5 playing a much larger role than the Rel TFs. It is also noteworthy that the other γ_c cytokines, IL-4, IL-7, IL-9, IL-15, and IL-21 do not compensate for the loss of IL-2 signals, even though they also all activate STAT5. Thus, the IL-2 (-/-), IL-2Rα (-/-) and IL-2Rβ (-/-) mice all develop a similar immunocompromised/lymphoproliferative autoimmune syndrome.^1–3 By comparison, deletion of the other γ_c cytokines does not lead to similar autoimmune abnormalities. Accordingly, there is something extraordinary about IL-2 signaling that is not shared by the other γ_c cytokines, even though they may activate similar signaling pathways…

In 2000, the gene responsible for the scurfy syndrome (sf) was cloned by Fred Ramsdell's group in Seattle, Washington in collaboration with J. Wilkinson of the group from Oak Ridge Tennessee, which had originally identified the mutation.¹ The protein encoded by this gene was found to be a new member of the forkhead/winged-helix family of transcriptional regulators, which has over 80 members, and was designated FOXP3. Also, it was found to be highly homologous to an orthologous gene in humans. In scurfy mice, a frame-shift mutation results in a product lacking the carboxy-terminal forkhead domain. Genetic complementation demonstrated that the protein product of FOXP3 could restore normal immune homeostasis…

Confounding this new definition of Tregs were data that accumulated subsequently, concerning FOXP3 expression by human T cells. In contrast to the reports that found FOXP3 expression restricted to murine CD4⁺CD25⁺ cells, and not influenced by activation via TCR/CD28 stimulation, peripheral mature human CD4⁺CD25^- T cells activated via TCR/CD28 were found to express FOXP3.¹ Moreover, human CD8⁺ T cells were also found to express FOXP3.^2,3 Therefore, as FOXP3 mutants of both mice and man results in a very similar fatal autoimmune syndrome, these results called into question the concept that only CD4⁺CD25⁺FOXP3⁺ T cells function to actively suppress potentially self-reactive T cells. Thus, would one need to extend the definition of Tregs to both CD4⁺ and CD8⁺ CD25⁺FOXP3⁺ T cells? Also, if FOXP3 expression can be activated by TCR/CD28 signaling, does that mean that FOXP3 expression does not delineate a separate cell lineage? Can all T cells become potential Tregs, if they can express FOXP3 and CD25, as well as the other cell surface markers that delineate this phenotype (i.e. CTLA-4, GITR)? Moreover, what are the critical stimuli that lead to FOXP3 expression? In this regard, it is especially noteworthy that early on investigators speculated that the expression of FOXP3 by an antigen-activated T cell could act as a natural feedback loop that would prevent unrestricted cytokine production and inflammatory reactions, particularly in response to auto-antigens.²…

In Chap. 8, the metabolism of IL-2 and IL-2Rs was reviewed. To recapitulate, only high affinity trimeric IL-2Rs are internalized, and essentially only when triggered by IL-2 binding. The t_1/2 for internalization is only 15 minutes. The quaternary IL-2/IL-2R complex takes a clatherin-independent internalization pathway, whereby the IL-2R α-chain is recycled to the cell surface, while IL-2 along with the IL-2R β-chains and γ-chains are trafficked to lysosomes and degraded. The end result of this IL-2/IL-2R metabolism is a very rapid diminution of IL-2 concentrations, such that if IL-2 production is discontinued for any reason, IL-2R⁺ cells rapidly consume and degrade IL-2, thereby providing a built-in mechanism that guarantees cessation of IL-2 signaling of proliferative expansion. Moreover, in vitro the cell surface density of the IL-2R α-chains remains high, while the cell surface density of the β-chains and γ-chains decreases to a new steady state of ~50% of the initial densities within two hours…

Given that FOXP3 expression in the thymus is purportedly important in the generation of nTreg cells, and in view of the fact that FOXP3 expression is inducible in vitro in mature peripheral T cells (iTregs) via activation by TCR/CD3/CD28 stimulation, the molecular pathways that control FOXP3 gene expression become relevant. Because the kinetics of FOXP3 expression after engagement of the TCR resembled the delayed kinetics of CTLA-4 expression, we conjectured that although the TCR complex (signal #1) might initiate FOXP3 gene expression, there might also be contributions from the co-stimulatory pathway (signal #2), as well as via the IL-2/IL-2R JAK1/3 STAT5 pathway (signal #3). In this regard, Ritz and colleagues first showed that IL-2 regulates FOXP3 expression in human CD4⁺CD25⁺ T cells through a STAT5-dependent mechanism,¹ and Farrar's group showed that the IL-2Rβ chain-dependent activation of STAT5 is necessary for the expression of murine nTreg FOXP3, thereby suggesting that either IL-2 or IL-15 are involved.² However, the molecular mechanisms responsible for expression of FOXP3 by mature, peripheral TCR-activated T cells, and the consequences of this expression for T cell function had not been examined in detail…

The experiments detailed above are important, in that they show that within a mixed cell population, if one blocks the IL-2/IL-2R interaction, TCR triggering together with any other cytokines already present in situ or produced by any of the cells are insufficient to induce FOXP3 expression. However, these data do not adequately delineate the signaling pathways or their roles in actually promoting FOXP3 expression. Utilizing either human or murine T cells, it has been shown that purified mature peripheral CD4⁺CD25^-FOXP3^- T cells can be made to yield 100% FOXP3⁺ cells provided they are stimulated by solid-phase anti-CD3/28 and cultured for several days in IL-2 + TGFβ.^1–3 Also, in these experiments, it is critical to use solid-phase anti-CD3, as soluble MoAb fails to activate FOXP3 expression in murine cells. This is particularly noteworthy, in that solid-phase anti-CD3 has always been considered to produce a very "strong" signal. Based on the hypothesis that the TCR is a mechanoreceptor and is triggered by torque forces, the use of solid phase anti-CD3 may well provide for maximum torque. In addition, the exogenous addition of TGFβ is just as critical for FOXP3 expression by murine T cells.⁴ However, if one uses T cells from IL-2 (-/-) mice they do not become FOXP3⁺ unless IL-2 is supplied exogenously, clearly emphasizing a critical role played by IL-2.³…

As FOXP3 expression is controlled by the TCR and IL-2, and therefore restricted to T cells, the effects of FOXP3 expression on T cells is the next obvious question. Two functions have been attributed to FOXP3:

1) the restriction of cytokine gene expression by FOXP3⁺ cells, thereby resulting in energy, and

2) the FOXP3⁺ T cell "active suppression" of FOXP^- cell cytokine production, especially IL-2, resulting in their diminished proliferation.

As demonstrated, the expression of FOXP3 and IL-2 is mutually exclusive, so that it appears that IL-2 induces its own inhibitor, a prerequisite for a classic internal hormonal control system…

At this time, it has become dogma that Treg cells "actively suppress" the immune response, although the mechanism(s) whereby these cells effect their suppression remain elusive. As already detailed, some investigators maintain that Tregs suppress the expression of the B7 co-stimulatory molecules on APCs by a cell contact-dependent mechanism that remains to be elucidated at the molecular level. However, this lack of effective APC co-stimulation of antigen-activated T_eff cells retards their production of IL-2, thereby attenuating their clonal proliferative expansion, the hallmark of a systemic immune response, as well as the hallmark of Treg suppression of T_eff cells.¹ Alternatively, the Treg "passive" binding, internalization and degradation of IL-2 produced by T_eff cells may well account for much, if not all, of the suppression of T_eff cell proliferation.^2,3 Of course, these two proposed mechanisms are not necessarily mutually exclusive…

Twenty-five years ago, when we first could ask the question whether it makes any difference if a cell expresses just a few IL-2Rs or many IL-2Rs, only the IL-2Rα chain was known. Of course, as detailed earlier, the answer was an unequivocal "yes!" It does indeed make a difference.¹ Because cells differed in the density of IL-2Rα chains as much as three orders of magnitude, some cells could have only 100 sites/cell, while others could have as many as 100,000 sites/cell, with most cells distributed about a mean of ∼1–10,000 sites/cell. The difference that we could uncover at the time, using G_0/1 synchronized cells, was that the IL-2Rα chain density determined how rapidly a cell progressed through G₁, passed the R-Point, and began to replicate DNA. The cells with the greatest density of IL-2Rα chains were the fastest. We concluded that the cell somehow counts the absolute number of triggered IL-2Rs over time, and only passes the R-Point when a critical number is surpassed…

In 1972 Sir MacFarlane Burnet proposed that autoimmunity results from a genetic predisposition due to germline mutations that are propagated for the most part as silent heterozygous mutants, combined with random somatic mutations in relevant genes.¹ Of course, at that time the nature of the important molecules responsible for the generation of an immune response had yet to be discovered. Moreover, molecular genetics had yet to come into being. Therefore, exactly which genes might be responsible for this genetic etiology of autoimmunity remained entirely obscure and was unapproachable…

Given Burnet's hypothesis that a "forbidden clone" of auto-reactive lymphocytes could be responsible for autoimmune destruction of specific cells, tissues, and organs, what evidence has accumulated to date that supports such a hypothesis? The most data accumulated in this regard are found in studies of T1DM…

As a result of progress that has occurred over the past 50 years, we now have a reasonably complete understanding of the molecular pathogenesis of at least one type of cancer, i.e. chronic myelocytic leukemia (CML) (reviewed in Ref. 1). CML results from a mutation that circumvents the normal cytokine/receptor signaling of quantal cell cycle progression. The mutation, originally discovered by Peter Nowell in 1960 and termed the Philadelphia (Ph) chromosome,² results in the constitutive activation of a protein tyrosine kinase (PTK), the cellular proto-oncogene c-Abl,³ which persistently phosphorylates one of the src family kinases, Hematopoietic cell Kinase (HcK), which in turn persistently phosphorylates and activates STAT5.⁴ Persistently activated STAT5 then circumvents the normal hematopoietic cytokine/receptor quantitative control of the cell cycle, and results in the continuous expression of genes necessary for both cell cycle progression (e.g. the cyclin D genes), and antiapoptotic genes important for cell survival (e.g. BclX).⁵…

The following sections are included:

• Epilogue

• Index