Leukemia: In the memory of Sohrab Sepehri and for the little Shauna

Introduction:

Leukemia or the white blood cells cancer are either acute or chronic. Either of these types are divided to lymphocytic or lymphoblastic, myeloid or myeloblastic, hence ALL (Acute Lymphoblastic Leukemia), CLL (Chronic Lymphoblastic Leukemia), AML (Acute Myeloblastic Leukemia), or CML (Chronic Myeloblastic Leukemia). In leukemias the white blood cells that are in charge of the body immunity and produced in the bone marrow, are not fully developed, abnormal and in produced in great numbers. Therefore the immunity of the inflicted individuals are seriously affected and present with a variety of infections, bleeding, bruises, fever, etc. ALL is most commonly occur in children and is the most common blood cancer in this age group, but the other types of leukemias, AML, CLL and CML are more common in adults. While ALL is the best prognostic of these leukemias, the rest of the three have poorer prognosis, specially AML. The cause of these common blood cancers are not fully known, but inheritance and environmental factors such as radiation in its etiology have been proposed. This is while more than 2 million people worldwide are affected with leukemias with a mortality of more than 350,000 per year.

 

Sohrab Sepehri, a Persian poet and painter whose a few of his verses and paintings are posted here in between the texts, died at age of 51 from this killing cancer. He was born in a desert town of Iran, Kashan, but loved life and nature like no one else. He excelled more in poetry than painting that was his original art career, though his real life job was a teacher as none of his art work could provide for him and he did not write or paint for living. As you read a few of his poems here, he offered the poetry an imagery quality as if painting the words while versing. His poetry has been translated into many languages including English, French, Spanish, German, Italian, Swedish, Arabic, Turkish and Russian among others. He is more closer to Rumi, the ancient Persian poet, and his thoughts were more like sophism and Buddhism.

 

Shorab Sepehri

And Shauna is a little girl only 7 years old who at this very moment struggles with leukemia, and under chemotherapy has lost all her hair, wearing wig, her kidneys have been damaged and had to go under dialysis, her liver and nerves have been affected with treatment, and after all she has not cured yet. But she is positive, loves life and animals, specially dogs, cats and the fish in my office aquarium, when she comes in with her mom who is under my care for the treatment of the burden of care of her and her older brother who suffers from autism. Shauna also loves the nature as Sohrab did, and if she survives her killing cancer, perhaps one day she will be a poet, painter or both!

Another Victim of Mutation:

Leukemia like other cancers is another victim of gene mutations. As the nature takes care of itself, there is a “tumor suppressor gene” that over time has evolved in our system like other immune factors such as white blood cells themselves that defend our body against foreign invasions mostly by different microbes. But like in autoimmune disorders that the T-cells and other immune factors attack its own system, specific mutations in the cell divisionary process of white blood cell precursors, i.e. the stem cells, by microbial invasions or radiations is the pathophysiologic process of leukemia development.

 

The disturbances in the mitotic cell (cell division) process of white blood cells underlying Leukemia has been recognized for more than half a century, but mostly were linked to chromosomal abnormalities and not genetic mutations. (1) But soon this misconception was corrected by the theory that in fact they are the genetic factors that cause chromosomal breakage and structural rearrangements, but yet the pathophysiology of the genetic changes underlying these changes were not elucidated. (2) By early 1970’s the role of microbial invasion is the causation of cancers in general was proposed initially through RNA viruses causing genetic mutations and producing tumors in lab animals such as mice, hamsters, cats, rats, and chickens. (3) By mid-1970’s, errors in DNA replication was proposed as the underlying pathophysiologic mechanism of progression of human leukemic lymphocytes, for example by avian myeloblastosis virus. (4) At almost the same time the mutation in mitochondrial DNA was also proposed to have some etiologic role in the causation and progression of malignant cells including leukemia, but still within animal studies. (5)

 

Based on these early discoveries, research soon by the late 1970’s identified the pre-leukemic stage of hemopoietic dysplasia, or dysplasia of white blood cells about one year ahead of time before the onset of clinical symptoms that was a medical breakthrough. (6) By the mid-1980’s the genetic mutations of T-cell lymphocytes was proposed to cause the damage, causation and propagation of most oncogenic cells in the cell lineage of both leukocytes (white blood cells) and lymphocytes, causing most leukemias and lymphomas. (7) Soon the clinical use of interferons (e.g. alpha, beta & Gamma) that are signaling proteins released by the host cells in defense to the microbial invasions by viral and bacterial pathogens was proposed in the successful treatment of cancers including leukemias. (8)

 

Leukemia is one of the few cancers that are not only caused naturally through the genetic mutations by microbial invasions, but un-naturally by extreme radiations, most importantly through bombings. As if microbial attacks on our beings are not sufficient for our diseases and misery that humans, starting from Americans in the World War II initiated attacking by atomic bombs on Hiroshima and Nagasaki, causing many leukemias and other cancers in Japan. These types of leukemias cause damage to the stem cells so disrupts the differentiation of blood and immune cells and also cause complex chromosomal abnormalities. (9) Besides the well-known increase of leukemia as a result of atomic bombardments, there also have been demonstrated increases in cancers of the lung, breast, esophagus, stomach, colon, ovary, urinary bladder, and multiple myeloma among others. Sensitivity to radiation, in terms of cancer induction, is higher generally in younger people, so more children, adolescents and young adults were affected in Japan after the drop of atomic bombs by Americans. (10)

 

Perhaps leukemia particularly the chronic types is a bridge between malignancies or cancers and autoimmune disorders. Since blood cells and autoimmune cells are originated and differentiated from stem cells, there is a close cytopathogenic link between leukemic cells and autoimmune antibodies. Some of these autoantibodies are related to other autoimmune disorders such as RF (Rheumatoid Factor) related to Rheumatoid Arthritis (RA). (11) Interestingly these linked autoimmune disorders such as RA are systemic and affecting the whole body and different organs as is the leukemia itself. This amazing natural link that could go pathologic through mutations by microbial or other foreign invasions or disruptions have become the source of treatment for many autoimmune disorders and cancers, by the means of stem cell transplantations.

 

In the search of an early identification of the Victims:

Although this question may look like a billion dollar question to identify victims of leukemia early on before the clinical manifestations of the disease, but that has been a proposed and strenuously worked on possibility, not just for leukemia but for many other malignancies and autoimmune disorders. While this may sound searching for genetic factors, but genetics or inheritance of leukemia, other oncogenes and autoimmune diseases are so rare that scientific attentions have for long been directed towards other factors, particularly epigenetic. (13) While genetic alone is not sufficient to cause leukemia, environmental factors such as microbial invasions do not seem to be sufficient for such malady, though necessary. For example the most virus linked to leukemia and lymphomas, the human T-cell leukemia-lymphoma virus subgroup 1 (HLTV-1) causing the transformation of while blood cells to leukemic in a few weeks is a rarity. (14) Therefore as it has been in the case of other malignancies and autoimmune disorders, scientists have been exploring the interaction between the susceptibility of the individuals (genetics) and the environmental insults such as microbial invasions, or the epigenetics.

 

By 1989 in the case of leukemia scientists discovered that Retinoic Acid, a metabolite of Vitamin A and its receptor, Retinoic acid Receptor alpha (RAR alpha) are involved from the very embryonic stage in the development, cell differentiation and even gene transcriptions. (15-17) In the case of leukemia, RAR alpha has been identified in most human leukemic cells regardless of the type of biologic response to retinoic acid. (18) Therefore this sensitive receptor that perhaps has been created by mutation of microbial invasions seems to be the seed of production of leukemic cells. While the different derivatives of retinoid have been applied in the treatment of different humans disease specially skin dermatoses such as acne for long, and recently in the treatment of different malignancies, there is a double edge story to this vitamin metabolite. (19) Like any other vitamins and their metabolites that are necessary for survival and well functioning of body cells and systems even at a molecular level, the excess of retinoid could be detrimental. (20)  

 

The leukemia molecular research such as the above in fact has led scientists to further discovery of the epigenetic mechanisms of cancers and autoimmune diseases etiology, maintenance and progression. Since leukemia is a disordered cell differentiation at the stem cell and early embryonic developmental stages, with a significance for the role of vitamin A metabolites (21), the search for further discovery of other trace elements such as vitamins in the regulation and differentiation of different cells and organs have been an area of huge interest in the scientific arena. Along this path, the epigenetic role of other vitamins such as Vitamins C, D & B in the causation of some cancers, autoimmune and even other diseases such as neurodegeneratives have been established. (22-25) As briefly denoted earlier, while vitamins are vitals in the normal healthy cells and organs differentiation and development, they are all time-and-stage of life dependent, and needed in minute amount. Therefore an excess intake of vitamins could not be only therapeutic and healthy, but destructive and causing diseases.      

 

Although mutations could sound the answer to the etiology of leukemia like many other malignancies and autoimmune disorders, the etiologic formulations of these diseases are more complicated. First of all not all mutations are pathogenic or bad, but there are as well good or evolutionary mutations or creation of variations for survival and adaptation. (26-31) Second of all the presence of pathogenic, faulty or bad mutations alone is not sufficient for disease production. A mutation to cause a disease such as leukemia needs to occur at a sensitive timeline or time window. That is why an early mutation causes a disease or cancer in childhood such as ALL, while a later time mutation causes a later onset disease or cancer such as CLL in adulthood. (32) The accumulation and persistence of mutations in the absence of tumor suppressors or in the presence of tumor progressing factors is another important parameter in the phenotypic development of gene mutations into mature clinical signs and symptoms of diseases and cancers. (32) Moreover there are progressing or facilitating factors that promote or expedite the production of cancer or autoimmune disorders, such as smoking in case of lung cancer, constipation in case of colorectal cancer or inactive or old age brain in case of Alzheimer’s disease. (33-35)

 

Therefore for early detection and prevention of cancers such as leukemia and other autoimmune disorders, while the genetic susceptibilities and biological invasions could be hard to control and prevent, the detection and prevention of facilitating and progressing factors could be easier. Now lets take a step back and find out how the microbial invasions in a susceptible individual can cause leukemia. Since leukemia is a malignancy of the stem cells that give rise to malignant while blood cells, the microbial invasions need to happen in embryo, at an early time of cell differentiation and development. Depending on the timeline or time window of the invasion, the result will be an early childhood leukemia such as ALL or a later age ones such as CLL or CML in adults. Now lets get into the detail of this organized invasion.

 

Microbial invasions of the embryo and the stem cells:

The viral causation of leukemia and other stem cells malignancies have long been known and suspected in animals such as mouse, chickens and others since early 1950’s. (36-38) These animal stem cells malignancies such as leukemia have been well studied and shown to be transmissible. The first virally caused leukemia was reported in a 7-year-old child by M. G. Smith in 1956. (39) Cytomegalic inclusions produced by the human salivary gland virus that was detected in this child, usually passes from the mother to the infant and could result in serious complications such as life threatening pneumonia, persistent hepatitis, failure to thrive and death. Soon other stem cells malignancies such as lymphosarcoma were associated with cytomegalic inclusion disease, specially in children. (40) It was demonstrated that not only some viral oncogenes are transmissible within the same or across species, but what may cause mild pathology in one species, it could cause severe ones such as cancers like leukemia in another. (41) While by 1960’s there had not been any direct proof of causation of Leukemia or other stem cells malignancies with viral or microbial transmissions in human, these malignancies among the animals and humans were so histologically similar, that such deduction was suspected. (42)

 

Soon by 1970’s the popularity and conviction of viral etiology of human cancers, starting initially with such hypothesis in leukemia, led to the discovery of such viruses. The first of these viruses, were RNA viruses that were labeled as “leukoviruses” or “oncornaviruses”. (43) Of the characteristics of these viruses are that unlike DNA viruses, when invaded the victim, simultaneously transform the host cells and replicate themselves, so that the karyotype of the tumor eventually becomes that of the host rather than that of the virus. Hence distinguishing between the proliferative and neoplastic processes would be difficult. (44-45) In May 1977, Charlotte Friend, a pioneer in the discovery of viral oncogens, particularly in the case of leukemia in a presidential address of the topic of tumor virology to the scientists audience of the center for the experimental cell biology, revealed that how she and other pioneers in the field were initially opposed by misbeliefs others with mockery. (46) She bravely disclosed that at that era of skepticism, she and others in their labs went farther to present the effectiveness of vaccination with the inactivated virus in protecting mice against the development of leukemia. (47)   

 

But soon non-believers were transformed to believers and a race for more discovery in the viral oncogeny, specifically in the case of leukemia, lymphoma and other stem cell malignancies were prompted. Since there was no trace of direct hereditary or genes involvement in the causation of leukemia and the immune responses of families even the mothers of afflicted children with ALL were different, and no direct vertical transmission was easily found, the viral oncology developed farther. (48) It was discovered that the tumorigenic viruses are of two types of endogenous and exogenous. The endogenous or type 1 already living inside the hosts, perhaps invaded long time ago and are not necessarily oncogenic but under temperate conditions become as such or type 2. While the type 1 non-oncogenic has perhaps transmitted intra-species, the type 2 tumorigenic ones transmit inter-species. (49) As a result several transcriptional and post-transcriptional factors and regulators were discovered. (50)

 

The search for the blocking factors against the progressing tumorigenic factors commenced and interferons, and other T-cell leukemia/lymphoma virus (HLTV-1) antibodies were discovered and the path for successful treatment of stem cells malignancies initiated. (51) The hypothesis of receptor mediated leukaemogenesis in late 1970’s, brought in a new depth into the understanding of tumorogenesis. This model, while faced a widespread skepticism, proposed that the viral oncogene, or antigen of viruses causing malignancies have specific host receptor binding capacities. (52) An analogous autocrine mechanism of cell receptor binding to promote normal cell proliferation, was used to explain the tumors such as leukemia’s progression, survival and metastases. (53-54)   

While the retroviruses and other exogenous viruses had been known for long in tumorogensis, the endogenous retroviruses that live within their host such as humans for thousand of years and comprise 5-8% of our genomes, and not usually pathogenic, were discovered to be as such in certain circumstances. These retroviruses enter the host and if both sides adapt to each other, they will be not only pathogenic, but promoting health and evolution and complexity of the genome. But in case of mal-adaptation, specially early on and by young viruses, they turn to be invaders and pathogenic, particularly to the immune system, causing auto-immune disorders and cancers such as leukemia. (55-57)

Something that we knew for long and the common sense approve was the equation between the immune system of the host and microbial invasion to cause damage. By learning about the tumorogenic or pathogenic mechanism of viruses, specially retroviruses and particularly the endogenous ones, soon the sophisticated formula or recipe of these viruses causing autoimmune disease and cancers were explored. The aftermath of the fact became obvious as in the case of infections, that the viruses for entry into the cells and being pathogenic and carcinogenic, they need weakness in the autoimmune system such as “Major Histocompatibility Complex” (MHC), T-Cell helpers, CD4 &CD8 T cells and other antibody responses. This soon paved the path for the treatment and recovery by potentiating the immune system by vaccines and infusion of anti-viral or antibody agents such as interferon. (58-60) Moreover there are cell proteins needed on both sides of the invaders and the hosts that regulate the transcription or transformation of a normal cell such as stem cell in the case of leukemias and lymphomas, e.g. tax protein, HBZ protein and LMO2 protein. (61-62)

Soon the invading viruses such as retroviruses were used for gene therapy, particularly in stem cell therapy of cancers such as leukemia. Lentiviruses such as HIV with a long incubation period were used to infiltrate cells such as stem cells as vectors to produce disease and oncogene protecting factors such as DNAs and RNAs and regulatory elements to alter the course of autoimmune diseases and cancers. (63-64) Initially described at the onset of the 90’s, chimeric antigen receptors (CARs) are recombinant receptors transferred in various T cell subsets, providing specific antigens binding in a non-major histocompatibility complex restricted manner, and effective on a large variety of human leukocyte antigen-divers cell populations. Once transferred, engineered T cells act like an expanding “living drug” specifically targeting the tumor-associated antigen, and ensure long-term anti-tumor memory. Over the last decades, substantial improvements have been made in CARs design. CAR T cells have finally reached the clinical practice and the first clinical trials have shown promising results. In acute lymphoblastic leukemia, high rate of complete and prolonged clinical responses have been observed after anti-CD19 CAR T cell therapy, with specific but manageable adverse events. (65)

Research into stem cells and stem cells therapy grew out of the seminal work of Ernst McCulloch and James Till at the University of Toronto in 1960s. (66-67) But despite the advent and common clinical popularity of stem cell therapy and transplantations in different cancers including leukemias, the stem cell cancer persistence, drug intolerance, drug resistance, and advanced-phase disease represent challenges to the total cure of these diseases that hence demand for more fundamental treatment and prevention strategies. (68) Therefore gene therapy and interception of the carcinogenic pathways of myelodysplastic syndromes, or undoing the mutations by techniques such as DNA hypomethylating agents are warranted and more promising in the future. (69)

Conclusion:

Leukemias being a cancer of blood cells, originating from a faulty stem cells differentiation perhaps from an early embryonic life stage, has its special significance. The significance of leukemias are multi-levels, relating to stem cells, an early embryonic mutation by microbial invasions or others such as radiations. Due to its early embryonic nature and course of development, leukemias could be seen across life span. Moreover due to its inception in the embryonic stem cells, and interception into many autoimmune processes involved in the cells and tissues differentiation across life span, and cross species, much has been learnt about this primal disease that a very brief depiction of it was presented here.

 Research into Leukemias, specially at a molecular level have helped scientists to discover more about stem cells, cells and tissues differentiation process and any interceptions such as mutations by microbial invasions in between. Hence novel treatment such as stem cells therapy, transplantations, and gene therapies not only for this disease, but for many other cancers and autoimmune diseases have been invented and progressed over years and are still ongoing. In fact mostly from leukemia’s research, we have learnt the pathogenesis of other malignancies and autoimmune disorders and the future research need to focus more on this direction.

 Finally though we continue to advent and progress different novel treatments of all stem cells malignancies and autoimmune disorders, the big dilemma is if we can stop and prevent the faulty stem cells and tissues development. In this arena we need to find a negotiating way if any with the microbial invasions, such as retroviruses that have lived on the earth for billions of years and are part of our genomes. Is that possible at all?! Is our advanced and highly evolved and specialized brain capable of defeating these tiny RNA viruses?! In this challenge far into the unknown future who will be the winner, or will be any common ground for both to live in peace? This is a big question as big as the nature itself, and perhaps a choice between intelligence and random, in the fight for survival and adaptation.

 Dr. Mostafa Showraki, MD, FRCPC                                                             Lecturer, School of Medicine, University of Toronto                                    Author: ADHD:Revisited Book                              Adhdrevisited.com/medicinerevisited.com       

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