Acute+Myeloid+Leukemia

Hamda Khan Professor Islas Bio 179: Cancer Biology 17 April 2015

Every year, an estimated 43,000 people in the United States are diagnosed with leukemia. This year Andrew Lee, a thirty-five-year-old white male has become part of the count as he is diagnosed with the most aggressive and rare form of leukemia: acute megakaryocytic leukemia (AMKL). Andrew, a husband and a father of three lovely children, lives a very healthy lifestyle. He eats a meticulously planned and balanced diet. He also indulges in regular exercise, at minimum running four miles a day. He works as an engineer for the Products Safety Commission. He very recently switched into this field and is located in a very safe and heavily monitored environment. Additionally, he has no known family history with cancer. Andrew has been sick on and off for over two months and initially came in to get tested for infectious mononucleosis (mono). His ongoing symptoms have been fatigue and frequent illness. Correspondingly, his blood work revealed that his leukocyte count was abnormally low, deeming him neutropenic. This diagnosis is very irregular and doesn’t align with the common understanding of leukemia. Leukemia tends to be the over production of abnormal and underdeveloped blood cells. However, Andrew’s tests show that he has little to no count of white blood cells. Though he didn’t exhibit other common symptoms of AMKL: bone pain, unusual bleeding, and frequent bruising, his affinity for infections and the development of a fever led to his immediate admittance in the air locked Bone Marrow Transplant ward.
 * Fighting Acute Myeloid Leukemia-M7 **

Andy’s diagnosis has been very tricky. Multiple bone marrow biopsies have been done to properly classify his leukemia. We have found a prevalent t(11;19) chromosomal translocation in his white blood cells. A chromosomal translocation is an abnormality in which segments of non-homologous chromosomes are exchanged. In Andy’s case, chromosomes eleven and nineteen have rearranged parts. This translocation is problematic because it has mixed phenotypes and can be linked to multiple acute leukemias. It is essential that we are able to correctly distinguish the subtype of leukemia that Andy has to ensure that we pursue the most effective treatment. The neutropenia, along with the specific chromosomal translocation, are irregularities that have made the medical team hesitant about their diagnosis. However, with the fifth bone marrow biopsy we have concluded that Andy indeed has Acute Megakaryoblastic Leukemia (AML M7) with a t(11;19) chromosomal translocation.

In hopes of understanding the depth of the cancer, we are looking into the risk factors that may have contributed to Andrew acquiring AMKL. His gender for instance predisposes him to AMKL. The reason for this is not well understood. Moreover, he neither has nor has family history of congenital syndromes. Congenital syndromes such as Down Syndrome tend to be associated with AMKL. The association between the diseases isn’t known but literature review indicates that if AMKL is present in conjunction with congenital diseases, the prognosis is improved significantly. Also, Andrew has no indication of any previous abnormalities on his medical records. There is also no sign of any blood disorders in his immediate family. The most unique and applicable risk factor may be his exposure to carcinogens. AMKL is associated with experience with high levels of radiation and or harsh chemicals like benzene. Though Andrew currently works in the Products Safety Commission, ensuring that toys are safe for children, he has previously been employed as a nuclear engineer. He spent approximately five years in the nuclear navy. Nevertheless, there is no known record of Andrew being exposed to anything carcinogenic. We are continuing to study his bone marrow to advance our understanding of his translocation.

The prognosis for AMKL is very unfortunate. The five year survival rate for acute myeloid leukemia overall is a little below twenty-four percent. Furthermore, Andrew’s case may be even more challenging as he has developed infections in his neck and head. With the presence of infections, chemotherapy may prove to be fatal. He is also beginning to show symptoms of pneumonia. Fortunately, Andrew’s age may help him survive. Mostly infants and children acquire AMKL. The mortality rate amongst patients of a younger age is significantly higher in comparison to adults. On the other hand, children are more like to enter complete remission while adults tend to relapse through out their lifetime. Another providence for Andrew is that he doesn’t have any comorbidities, underlying diseases, to accompany his cancer. These diseases tend to speed up the progression of cancer and make it more sever. It is of course unfortunate that he developed cancer but his lack of predisposition ensures that he hasn’t passed on any mutagens to his children.

** Finding a Treatment ** To ensure that Andrew is given the most relevant and applicable treatment, we first have to better identify his translocation. The chromosomal translocation in Andy’s blood cells, t(11;19), is very rare and dangerous because the breakpoint occurs at the band q23. This chromosomal abnormality is inducing the production of MLL protein, which is making Andy susceptible to leukemia. The treatment has to be designed to either prevent or block production of MLL. The main treatments available for acute myeloid leukemia are chemotherapy, growth factors, radiotherapy and stem cell transplants. Chemotherapy is the most common option. It is the use of cytotoxic drugs to target and destroy cancer cells. However, in Andrew’s case it may prove to be ineffective or fatal. A study comparing Andy’s specific chromosomal translocation, called 11q23, to other translocations showed that patients with other translocations had better outcomes than patients with translocations involving chromosome 11, band q23. Given the standard chemotherapy induction and consolidation, the median survival for this study was seven months with no patients surviving long term. The study concluded that when faced with this translocation, patients should be given chemotherapy in combination with other accessible treatments.
 * Figure 1. CR Duration and survival for AML patients with 11q23 translocations**

Growth factors, another possibility for treatment, are naturally occurring stimulants for blood cell production in the bone marrow. A class of growth factors such as granulocyte colony stimulating factor (G-CSF) can be used to increase the number of white blood cells and stems cells in the blood stream. The side effects for growth factors are mild pain and itchiness at the injection site as well as bone soreness. The aches in the bones are due to the overproduction and crowding of the blood cells. In general, growth factors are a reasonable option for treatment. Radiotherapy is the use of high-energy radiation to kill cancer cells. Though nearly fifty percent of cancer patients are treated with radiotherapy, it is not a necessary option for Andrew. In his specific subtype of leukemia, radiation should be limited to patients whose cancer has spread to the central nervous system (CNS). This is so because radiation involves that use of microscopic waves that can enter the cells and mutate the DNA. In Andrew’s case this could be catastrophic because he already has a predisposition for translocations. Luckily for Andrew, his cancer has not spread to the CNS and thus he can steer clear of radiotherapy.

The last and perhaps the most successful treatment is a stem cell transplant. A stem cell transplant, also known as a bone marrow transplant, is a procedure in which mutated bone marrow is replaced with highly specialized stem cells. There are two types of stem cell transplants: autologous and allogeneic. An autologous transplant is when blood cells are extracted from the patient, treated to produce t-cells, and then transplanted back into the patient’s bloodstream. Allogenic transplants refer to getting stem cells from a non-related donor. Finding a donor through the National Marrow Donor Program can be complex because the database is trying to match people who have the same type of protein on their while blood cells, also known as human leukocyte antigen (HLA). This is problematic because there are six different antigens that are typed and must match. Sometime a five out of six match is acceptable, but not desirable. The side effects of a transplant are minimal as they include bone soreness, weight loss due to the diarrhea and skin rashes. Furthermore, a stem cell transplant is only a viable option for treatment if the leukemia has not metastasized into any of the organs.

In hopes of successfully eradicating the mutated cells, we will treat Andy with chemotherapy as well as a stem cell transplant. A stem cell transplant, similar to the use of growth factors, is more applicable for Andrew’s treatment because we intend to use sever chemotherapy. We will begin Andy’s treatment with the standard three rounds of chemotherapy. To put the cytotoxin directly into the bloodstream, a central line, a PICC or a portacath can be used. These are miniature tubes that are put in either the arm or chest and linked to a large vein. We have to be careful with the cytotoxin we choose because certain drugs can further the development of AMKL. Our intention is to kill of all cancerous cells with high doses of cytarabine. (Cytarabine has had the most success in clinical trails for AMKL) The complete removal of cancerous cells is to prepare for the stem cell transplant. The autologous stem cell transplant will follow the chemotherapy and will be the last step for Andrew’s treatment as he enters remission. We are counting on the autologous stem cell transplant to work because the alternate option: allogeneic transplant is much more difficult in accessibility as well as success. The side effects from the chemotherapy will be complete hair loss, bleeding, lethargy and changes in fertility. The hair loss and bleeding are because the cytotoxin targets cells that are continually reproducing. This of course includes hair as well the track from the mouth to the anus. The tiredness is from the loss of blood cells that can no longer provide enough oxygen to the body. The intensity of the chemotherapy will increase the side effects but it is necessary to ensure that all cells with translocations are killed.

For Andy’s sake, we are anticipating that the odds are in his favor and his autologous stem cell transplant will keep him in remission. Andy’s treatment is predicted to begin as soon as his infections in his neck and head are minimized. We cant begin chemotherapy yet because if we kill of all of his white blood cells (which is our intent) he will not be able to fight his infections. They might then prove to be more fatal than the cancer.

** Molecular Basis for AMKL ** Andy’s neutropenia and the development of AMKL can be attributed to translocations. Translocations, the exchange of segments on non-homologous chromosomes, are relatively common in cancer. There are two common pathways through which we see translocations occur. Translocations occurring in older age can be attributed to denigration of telomeres. Telomeres compose the ends of the DNA strand and ensure that chromosome ends are sealed and unable to interact with other chromosomes. Unfortunately, telomeres are only synthesized on the parent DNA strand because telomerase, the enzyme that makes telomeres, is turned off throughout our lifetime. Additionally, due to the nature of DNA replication the telomeres get shorter with every replication event. Therefore, in old age telomeres can degrade completely. This can provoke cell death but if the cell manages to live the unprotected DNA ends can fuse with one another, inducing translocation. The secondary pathway through which translocations occur is random breakage and fusion between chromosomes. The mechanisms that induce random translocations are poorly understood today. In Andy’s case we can hypothesize that the later pathway caused the translocations. He is a middle-aged man so it is safe to say that his telomeres are far from total degradation.

Though we don’t know what induced the translocation in Andy’s blood cells, we do know where it happened. This is key to understanding the cancer and applying appropriate treatment. Andy’s translocation involves chromosomes 11 and 19. The locus at which the mutation has occurred is identified as 11q23. The aberration at 11q23 affects the mixed-linage leukemia (MLL) gene. This mutation is extremely rare and can be observed in an estimated 3-4% of patients with AMKL. The MLL gene translates a histone methyltransferase. The histone methyltransferase is a regulatory protein that behaves as a transcriptional co-activator. Essentially, DNA is coiled around histones and condensed tightly into chromatin. Methylation of histones by methyltransferases leads to uncoiling or supercoiling of the DNA, allowing genes to be activated or repressed, respectively. The MLL gene methylates histone 3 at lysine 4 (H3K4) causing transcriptional activation of essential genes for survival and evasion of disease. Translocations at locus 11q23 disrupt the gene sequence for the MLL gene. Alternative splicing of the MLL gene produces various transcripts that ultimately introduce problems in proper and complete transcription of the gene. Andy’s cancer is predictably due to the splicing of the MLL gene at the promoter. The MLL gene is not being expressed in his genome. Without the MLL gene, there isn’t a methyltransferase present to activate the variety of key genes coiled around histone 3, leaving that genomic area silenced. The genes that tend to make up that specific area on the genome are downstream of nuclear factor-kB (NF), mediate the cell cycle and even play a role in hematopoiesis. Hematopoiesis is the composition of blood cellular components, more commonly known as blood stem cells. We can witness this phenomenon in Andy’s blood work. He has a substantial deficiency in his white blood cell count, which is likely due to the unsuccessful transcription of the hematopoiesis complex. Additionally, genes downstream of NF include growth factors, regulators of apoptosis, cell surface receptors and transcriptional factors and regulators. This further adds to the severity of Andy’s cancer. The MLL gene therefore has the capability of being extremely leukemogenic.

The treatment that we have selected for Andy is a direct response to the molecular basis for his cancer. The three steps intensive chemotherapy is to ensure that we kill off the insuffiecntly developed blood cells. We want to not only eradicate the chromosomal translocation but also the deformed blood cells. Blood cells that aren’t developed properly can be dangerous in the blood stream because they can throw off the immune system. Most likely due to the silencing of genes downstream of NF, the cellular receptors on these blood cells are mute. This would make it so these blood cells are not only improperly formed but they are also able to go under the radar of the innate immune response. Additionally, they would also be dividing rapidly. Unfortunately, cell cycle mediators are also under the influence of the MLL gene. Due to the translocation the Cyclic-Dependent Kinase inhibitors (CDK inhibitors) are more or less dysfunctional and they aren’t able to police the cell cycle. When there is an abnormality in the cell, the cell continues to divide because the CDK inhibitors aren’t able to notify that cell of the problems and give it a stop signal. Because of the extent of mutations that can be present in Andy’s blood cells, we are killing them all off. We will then give him an autologous stem cell transplant to replace his death blood cells. This form of treatment ensures remission because we are getting rid all instances of the mutation that the translocation introduces.
 * Table 1. Age distribution of AML with 11q23/MLL rearrangement compared with the total AML cohort                                                                                                                                                                                                                                                                 **

Andy’s cancer is as rare as it is deadly. The heterologous splicing of the MLL gene is catastrophic because it is upstream of a lot of absolutely essential genes. The severity of the cancer and the translocation is in that fact that the cells are able to mutate in a variety of ways in response to a single gene being silenced.

Andy’s battle with Acute Megakaryotic Leukemia has been long and dangerous. It has taken a physical and emotion toll on him and his family. Andy came in a strong, abled body and is leaving a frail, exhausted man. The silver lining of course is that Andy’s cancer is in remission. We continue to hope that his autologous transplant remains successful and that his cancer doesn’t come back. We will continue to do bone marrow biopsies every six months for the next two years to keep a close eye on his blood cellular components. We aspire to see normal levels of leukocytes. The statistics are on Andy’s side considering that over fifty percent of patients under forty-five that are treated for AMKL survive for five years or more. However, a prognostic factor for AMKL that may affect Andy’s outcome is the molecular nature of his cancer. The cancer was a result of genetic changes (translocations) in the leukemia cells. Assuming that there is a predisposition for random translocations, Andy could develop the same or different translocations throughout his lifetime. Only time will tell. As Andy returns home today he has been humbled by the emperor of all maladies and plans to do all that he can to ensure there is a strong support network for both patients and family members affected by cancer.