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III-64. The answer is C. (Chap. 105) The peripheral blood smear shows hypochromasia, macrocytosis, and a hypersegmented (>five lobes) neutrophil. These findings are typical for a megaloblastic anemia as seen in cobalamin or folate deficiency. The mean corpuscular volume is typically greater than 100 fL, and there is significant anisocytosis and poikilocytosis. There may also be leukopenia and thrombocytopenia that correlate with the degree of deficiency. Other less common causes of megaloblastic anemia include therapy with drugs that interfere with folate metabolism (methotrexate) or DNA synthesis (hydroxyurea, AZT, cytosine arabinoside, 6-mercaptopurine) and some cases of acute myeloblastic leukemia or myelodysplasia. Autoantibodies to ADAMTS-13 are associated with thrombotic thrombocytopenic purpura, which causes a microangiopathic hemolytic

anemia. Epstein-Barr virus infection is associated with large atypical lymphocytes, not hypersegmented neutrophils. Iron-deficiency anemia causes a microcytic hypochromic anemia.

III-65. The answer is B. (Chap. 106) Red blood cells (RBCs) use glutathione produced by the hexose monophosphate shunt to compensate for increased production of reactive oxygen species (oxidant stress), usually induced by drugs or toxins. Defects in glucose-6-phosphate dehydrogenase (G6PD) are the most common congenital hexose monophosphate shunt defect. If the RBC is unable to maintain an adequate level of glutathione during oxidant stress, hemoglobin precipitates in the RBC, producing Heinz bodies. Because the G6PD gene is on the X chromosome, almost all affected patients are males. G6PD deficiency is widely distributed throughout regions that are currently or were once highly malarial endemic. It is common in males of African, African American, Sardinian, and Sephardic descent. In most persons with G6PD deficiency, there is no evidence of symptomatic disease. However, infection, ingestion of fava beans, or exposure to an oxidative agent (drug or toxin) can trigger an acute hemolytic event. Bite cells, Heinz bodies, and bizarre poikilocytes may be evident on smear. The drugs that most commonly precipitate a G6PD crisis include dapsone, sulfamethoxazole, primaquine, and nitrofurantoin. The anemia is often severe with rapid onset after drug ingestion, and renal failure can occur.

III-66. The answer is B. (Chaps. 106 and 319) This patient’s lupus and her rapid development of truly life-threatening hemolytic anemia are both very suggestive of autoimmune hemolytic anemia. Diagnosis is made by a positive Coombs test documenting antibodies to the red cell membrane, but smear will often show microspherocytes, indicative of the damage incurred to the red cells in the spleen. Schistocytes are typical for microangiopathic hemolytic anemias such as hemolytic uremic syndrome (HUS) or thrombotic thrombocytopenic purpura. The lack of thrombocytopenia makes these diagnoses considerably less plausible. Macrocytosis and polymorphonuclear leukocytes with hypersegmented nuclei are very suggestive of vitamin B₁₂ deficiency, which causes more chronic, non–life-threatening

anemia. Target cells are seen in liver disease and thalassemias. Sickle cell anemia is associated with aplastic crises, but this patient has no known diagnosis of sickle cell disease and is showing evidence of erythropoietin response based on the presence of elevated reticulocyte count.

III-67. The answer is C. (Chap. 106) The peripheral blood smear shows microspherocytes, small densely staining red blood cells (RBCs) that have lost their central pallor characteristic of hereditary spherocytosis. Spherocytosis is almost the only condition with an increased mean corpuscular hemoglobin concentration. Hereditary spherocytosis is a heterogeneous RBC membranopathy that can be either congenital (usually autosomal dominant) or acquired; it is characterized by predominantly extravascular hemolysis in the spleen caused by defects in membrane structural proteins. This spleen-mediated hemolysis leads to the conversion of classic biconcave RBCs on smear to spherocytes. Splenomegaly is common. This disorder can be severe, depending on the site of mutation, but is often overlooked until some stressor such as pregnancy leads to a multifactorial anemia, or an infection such as parvovirus B19 transiently eliminates RBC production altogether. Acute treatment is with transfusion. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a cause of hemolysis that is usually triggered by the presence of an offending oxidative agent. The peripheral blood smear may show Heinz bodies. Parvovirus infection may cause a pure RBC aplasia. The presence of active reticulocytosis and laboratory findings consistent with hemolysis are not compatible with that diagnosis. Chronic gastrointestinal blood loss, such as caused by a colonic polyp, would cause a

microcytic, hypochromic anemia without evidence of hemolysis (indirect bilirubin, haptoglobin abnormalities).

III-68. The answer is D. (Chap. 106) Each of the listed diagnoses has a rather characteristic set of laboratory findings that are virtually diagnostic for the disease once the disease has progressed to a severe stage. The combination of portal vein thrombosis, hemolysis, and pancytopenia is typical for paroxysmal nocturnal hemoglobinuria (PNH). PNH is a rare disorder characterized by hemolytic anemia (particularly at night), venous thrombosis, and deficient hematopoiesis. It is a stem cell–derived intracorpuscular defect. Anemia is usually moderate in severity, and there is often concomitant granulocytopenia and thrombocytopenia. Venous thrombosis occurs much more commonly than in the population at large. The intraabdominal veins are often involved, and patients may present with Budd-Chiari syndrome. Cerebral sinus thrombosis is a common cause of death in patients with PNH. The presence of pancytopenia and hemolysis should raise suspicion for this diagnosis even before the development of a venous thrombosis. In the past, PNH was diagnosed by abnormalities on the Ham or sucrose lysis test; however, currently flow cytometry analysis of glycosylphosphatidylinositol (GPI) linked proteins (e.g., CD55 and CD59) on red blood cells and granulocytes is recommended. Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) both cause hemolysis and thrombocytopenia, as well as fevers. Cerebrovascular events and mental status change occur more commonly in TTP, and renal failure is more common in HUS. Severe leptospirosis, or Weil’s disease, is notable for fevers, hyperbilirubinemia, and renal failure. Conjunctival suffusion is another helpful clue. Acute promyelocytic leukemia is notable for anemia, thrombocytopenia, and either elevated or a decreased white blood cell count, all in the presence of disseminated intravascular coagulation.

III-69. The answer is A. (Chap. 106) Haptoglobin is an α-globulin normally present in serum. It binds specifically to the globin portion of hemoglobin, and the complex is cleared by the mononuclear cell phagocytosis. Haptoglobin is reduced in all hemolytic anemias because it binds free hemoglobin. It can also be reduced in cirrhosis and so is not diagnostic of hemolysis outside of the correct clinical context. Assuming normal bone marrow and iron stores, the reticulocyte count will be elevated as well to try to compensate for the increased red blood cell (RBC) destruction of hemolysis. Release of intracellular contents from the RBC (including hemoglobin and lactate dehydrogenase) induces heme metabolism, producing unconjugated bilirubinemia. If the haptoglobin system is overwhelmed, the kidney will filter free hemoglobin and reabsorb it in the proximal tubule for storage of iron by ferritin and hemosiderin. Hemosiderin in the urine is a marker of filtered hemoglobin by the kidneys. In massive hemolysis, free hemoglobin may be excreted in urine.

III-70. The answer is E. (Chap. 106) Hemolytic anemias may be classified as intracorpuscular or extracorpuscular. In intracorpuscular disorders, the patient’s red blood cells (RBCs) have an abnormally short life span because of an intrinsic RBC factor. In extracorpuscular disorders, the RBC has a short life span because of a nonintrinsic RBC factor. Thrombotic thrombocytopenic purpura (TTP) is an acquired disorder in which red blood cell and platelet destruction occur not because of defects of these cell lines but rather as a result of microangiopathy leading to destructive shear forces on the cells. Other clinical signs and symptoms include fever; mental status change; and, less commonly, renal impairment. Most acquired adult cases of TTP are associated with autoantibodies to ADAMTS-13 (or von Willebrand factor–cleaving protease). All cases of hemolysis in conjunction with thrombocytopenia should be rapidly ruled out for TTP by evaluation of a peripheral smear for

schistocytes because plasmapheresis is lifesaving. Other causes of extravascular hemolytic anemia include hypersplenism, autoimmune hemolytic anemia, disseminated intravascular coagulation, and other microangiopathic hemolytic anemias. The other four disorders listed in the question all refer to some defect of the RBC itself that leads to hemolysis. Elliptocytosis is a membranopathy that leads to varying degrees of destruction of the RBC in the reticuloendothelial system. Sickle cell anemia is a congenital hemoglobinopathy classified by recurrent pain crises and numerous long-term sequelae that is caused by a well-defined β-globin mutation. Pyruvate kinase deficiency is a rare disorder of the glycolytic pathway that causes hemolytic anemia. Paroxysmal nocturnal hemoglobinuria (PNH) is a form of acquired hemolysis caused by an intrinsic abnormality of the RBCs. It also often causes thrombosis and cytopenias. Bone marrow failure is a feared association with PNH.

III-71. The answer is C. (Chap. 107) Pure red blood cell aplasia (PRCA) is a condition characterized by the absence of reticulocytes and erythroid precursors. A variety of conditions may cause PRCA. It may be idiopathic. It may be associated with certain medications, such as trimethoprim– sulfamethoxazole (TMP-SMX) and phenytoin. It can be associated with a variety of neoplasms, either as a precursor to a hematologic malignancy such as leukemia or myelodysplasia or as part of an autoimmune phenomenon, as in the case of thymoma. Infections also may cause PRCA. Parvovirus B19 is a single-strand DNA virus that is associated with erythema infectiosum, or fifth disease in children. It is also associated with arthropathy and a flulike illness in adults. It is thought to attack the P antigen on proerythroblasts directly. Patients with a chronic hemolytic anemia, such as sickle cell disease, or with an immunodeficiency are less able to tolerate a transient drop in reticulocytes because their red blood cells do not survive in the peripheral blood for an adequate period. In this patient, her daughter had an illness before the appearance of her symptoms. It is reasonable to check her parvovirus immunoglobulin M (IgM) titers. If the results are positive, a dose of intravenous Ig is indicated. Because her laboratory test results and smear are not suggestive of dramatic sickling, an exchange transfusion is not indicated. Immunosuppression with prednisone, cyclosporine, or both may be indicated if another etiology of the PRCA is identified. However, that would not be the next step. Similarly, a bone marrow transplant might be a consideration in a young patient with myelodysplasia or leukemia, but there is no evidence of that at this time. Antibiotics have no role in light of her normal white blood cell count and the lack of evidence for a bacterial infection.

III-72. The answer is D. (Chap. 107) Aplastic anemia is defined as pancytopenia with bone marrow hypocellularity. Aplastic anemia may be acquired, iatrogenic (chemotherapy), or genetic (e.g., Fanconi’s anemia). Acquired aplastic anemia may be caused by drugs or chemicals (expected toxicity or idiosyncratic effects), viral infections, immune diseases, paroxysmal nocturnal hemoglobinuria, pregnancy, or idiopathic causes. Aplastic anemia from idiosyncratic drug reactions (including those listed as well others, including as quinacrine, phenytoin, sulfonamides, or cimetidine) are uncommon but may be encountered given the wide usage of some of these agents. In these cases, there is usually not a dose-dependent response; the reaction is idiosyncratic. Seronegative hepatitis is a cause of aplastic anemia, particularly in young men who recovered from an episode of liver inflammation 1 to 2 months earlier. Parvovirus B19 infection most commonly causes pure red blood cell (RBC) aplasia, particularly in patients with chronic hemolytic states and high RBC turnover (e.g., sickle cell anemia).

III-73. The answer is D. (Chap. 107) This patient has aplastic anemia. In the absence of drugs or toxins that cause bone marrow suppression, it is most likely that he has an immune-mediated injury. Growth

factors are not effective in the setting of hypoplastic bone marrow. Transfusion should be avoided unless emergently needed to prevent the development of alloantibodies. Glucocorticoids have no efficacy in aplastic anemia. Immunosuppression with antithymocyte globulin and cyclosporine is a therapy with proven efficacy for this autoimmune disease with a response rate of up to 70%. Relapses are common, and myelodysplastic syndrome or leukemia may occur in approximately 15% of treated patients. Immunosuppression is the treatment of choice for patients without suitable bone marrow transplant donors. Bone marrow transplantation is the best current therapy for young patients with matched sibling donors. Allogeneic bone marrow transplants from matched siblings result in long-term survival in more than 80% of patients, with better results in children than adults. The effectiveness of androgens has not been verified in controlled trials, but occasional patients will respond or even demonstrate blood count dependence on continued therapy. Sex hormones upregulate telomerase gene activity in vitro, possibly also their mechanism of action in improving marrow function. For patients with moderate disease or those with severe pancytopenia in whom immunosuppression has failed, a 3 to 4-month trial is appropriate.

III-74. The answer is B. (Chap. 107) Myelodysplasia, or the MDSs, are a heterogeneous group of hematologic disorders broadly characterized by cytopenias associated with a dysmorphic (or abnormal appearing) and usually cellular bone marrow and by consequent ineffective blood cell production. The mean onset of age is after 70 years. MDS is associated with environmental exposures such as radiation and benzene; other risk factors have been reported inconsistently. Secondary MDS occurs as a late toxicity of cancer treatment, usually with a combination of radiation and the radiomimetic alkylating agents such as busulfan, nitrosourea, or procarbazine (with a latent period of 5–7 years) or the DNA topoisomerase inhibitors (2 years). Both acquired aplastic anemia after immunosuppressive treatment and Fanconi’s anemia can evolve into MDS. MDS is a clonal hematopoietic stem cell disorder leading to impaired cell proliferation and differentiation. Cytogenetic abnormalities are found in approximately half of patients, and some of the same specific lesions are also seen in frank leukemia. Anemia dominates the early course. Most symptomatic patients complain of the gradual onset of fatigue and weakness, dyspnea, and pallor, but at least half the patients are asymptomatic, and their MDS is discovered only incidentally on routine blood counts. Previous chemotherapy or radiation exposure is an important historic fact. Fever and weight loss should point to a myeloproliferative rather than myelodysplastic process. About 20% of patients have splenomegaly. Bone marrow is typically hypercellular. Median survival varies from months to years, depending on the number of blasts in marrow and the specific cytogenetic abnormality. Isolated 5q- is associated with a median survival in years. Most patients die as a result of complications of pancytopenia and not because of leukemic transformation; perhaps one-third will succumb to other diseases unrelated to their MDS. Precipitous worsening of pancytopenia, acquisition of new chromosomal abnormalities on serial cytogenetic determination, increase in the number of blasts, and marrow fibrosis are all poor prognostic indicators. The outlook in therapy-related MDS, regardless of type, is extremely poor, and most patients progress within a few months to refractory acute myeloid leukemia. Historically, the therapy of MDS has been unsatisfactory. Only stem cell transplantation offers cure. Survival rates of 50% at 3 years have been reported, but older patients are particularly prone to develop treatment-related mortality and morbidity. Results of transplant using matched unrelated donors are comparable, although most series contain younger and more highly selected cases. However, multiple new drugs have been approved for use in MDS. Several regimens appear to not only improve blood counts but also to delay onset of leukemia and to improve survival.

Lenalidomide, a thalidomide derivative with a more favorable toxicity profile, is particularly effective in reversing anemia in MDS patients with 5q- syndrome; a high proportion of these patients become transfusion independent.

III-75. The answer is E. (Chap. 108) The World Health Organization’s classification of the chronic myeloproliferative diseases (MPDs) includes eight disorders, some of which are rare or poorly characterized but all of which share an origin in a multipotent hematopoietic progenitor cell, overproduction of one or more of the formed elements of the blood without significant dysplasia, a predilection to extramedullary hematopoiesis or myelofibrosis, and transformation at varying rates to acute leukemia. Within this broad classification, however, significant phenotypic heterogeneity exists. Some diseases such as chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), and chronic eosinophilic leukemia (CEL) express primarily a myeloid phenotype, but in others, such as polycythemia vera (PV), primary myelofibrosis (PMF), and essential thrombocytosis (ET), erythroid or megakaryocytic hyperplasia predominates. The latter three disorders, in contrast to the former three, also appear capable of transforming into each other. Such phenotypic heterogeneity has a genetic basis. CML is the consequence of the balanced translocation between chromosomes 9 and 22 [t(9;22) (q34;11)], CNL has been associated with a t(15;19) translocation, and CEL occurs with a deletion or balanced translocations involving the PDGFR-alpha gene. By contrast, to a greater or lesser extent, PV, PMF, and ET are characterized by expression of a JAK2 mutation, V617F, that causes constitutive activation of this tyrosine kinase that is essential for the function of the erythropoietin and thrombopoietin receptors but not the granulocyte colony-stimulating factor receptor. This essential distinction is also reflected in the natural history of CML, CNL, and CEL, which is usually measured in years, and their high rate of transformation into acute leukemia. By contrast, the natural history of P V, PMF, and ET is usually measured in decades, and transformation to acute leukemia is uncommon in the absence of exposure to mutagenic agents. Primary effusion lymphoma is not a myeloproliferative disease. It is one of the diseases (Kaposi’s sarcoma, multicentric Castleman’s disease) associated with infection with human herpes virus-8, particularly in immunocompromised hosts.

III-76. The answer is A. (Chap. 108) Polycythemia vera (PV) is a clonal disorder that involves a multipotent hematopoietic progenitor cell. Clinically, it is characterized by a proliferation of red blood cells (RBCs), granulocytes, and platelets. The precise etiology is unknown. Unlike chronic myelogenous leukemia, no consistent cytogenetic abnormality has been associated with the disorder. However, a mutation in the autoinhibitory, pseudokinase domain of the tyrosine kinase JAK2—that replaces valine with phenylalanine (V617F), causing constitutive activation of the kinase—appears to have a central role in the pathogenesis of P V. Erythropoiesis is regulated by the hormone erythropoietin. Hypoxia is the physiologic stimulus that increases the number of cells that produce erythropoietin. Erythropoietin may be elevated in patients with hormone-secreting tumors. Levels are usually “normal” in patients with hypoxic erythrocytosis. In P V, however, because erythrocytosis occurs independently of erythropoietin, levels of the hormone are usually low. Therefore, an elevated level is not consistent with the diagnosis. PV is a chronic, indolent disease with a low rate of transformation to acute leukemia, especially in the absence of treatment with radiation or hydroxyurea. Thrombotic complications are the main risk for PV and correlate with the erythrocytosis. Thrombocytosis, although sometimes prominent, does not correlate with the risk of thrombotic complications. Salicylates are useful in treating erythromelalgia but are not indicated in asymptomatic patients. There is no evidence that thrombotic risk is significantly lowered with their use in patients

whose hematocrits are appropriately controlled with phlebotomy. Phlebotomy is the mainstay of treatment. Induction of a state of iron deficiency is critical to prevent a reexpansion of the RBC mass. Chemotherapeutics and other agents are useful in cases of symptomatic splenomegaly. Their use is limited by side effects, and there is a risk of leukemogenesis with hydroxyurea.

III-77. The answer is A. (Chap. 108) Chronic primary myelofibrosis (PMF) is the least common myeloproliferative disorder and is considered a diagnosis of exclusion after other causes of myelofibrosis have been ruled out. The typical patient with PMF presents in the sixth decade of life, and the disorder is asymptomatic in many patients. Fevers, fatigue, night sweats, and weight loss may occur in PMF, but these symptoms are rare in other myeloproliferative disorders. However, no signs or symptoms are specific for the diagnosis of PMF. Often marked splenomegaly is present and may extend across the midline and to the pelvic brim. A peripheral blood smear demonstrates the typical findings of myelofibrosis, including teardrop-shaped red blood cells (RBCs), nucleated RBCs, myelocytes, and metamyelocytes that are indicative of extramedullary hematopoiesis. Anemia is usually mild, and platelet and leukocyte counts are often normal. About 50% of patients with PMF have the JAK2 V617F mutation. Bone marrow aspirate is frequently unsuccessful because the extent of marrow fibrosis makes aspiration impossible. When a bone marrow biopsy is performed, it demonstrates hypercellular marrow with trilineage hyperplasia and increased number of megakaryocytes with large dysplastic nuclei. Interestingly, individuals with PMF often have associated autoantibodies, including rheumatoid factor, antinuclear antibodies, or a positive Coombs test results. To diagnose someone as having PMF, it must be shown that he or she does not have another myeloproliferative disorder or hematologic malignancy that is the cause of myelofibrosis. The most common disorders that present in a similar fashion to PMF are polycythemia vera and chronic myelogenous leukemia. Other nonmalignant disorders that can cause myelofibrosis include HIV infection, hyperparathyroidism, renal osteodystrophy, systemic lupus erythematosus, tuberculosis, and bone marrow replacement in other cancers such as prostate and breast cancer. In the patient described here, there is no other identifiable cause of myelofibrosis; thus, chronic PMF can be diagnosed.

III-78. The answer is E. (Chap. 108) Thrombocytosis may be “primary” or “secondary.” Essential thrombocytosis is a myeloproliferative disorder that involves a multipotent hematopoietic progenitor cell. Unfortunately, no clonal marker can reliably distinguish it from more common nonclonal, reactive forms of thrombocytosis. Only 50% of patients with essential (primary) thrombocytosis have the JAK2 V617F mutation. Therefore, the diagnosis is one of exclusion. Common causes of secondary thrombocytosis include infection, inflammatory conditions, malignancy, iron deficiency, hemorrhage, and postsurgical states. Other myeloproliferative disorders, such as CML and myelofibrosis, may result in thrombocytosis. Similarly, myelodysplastic syndromes, particularly the 5q-syndrome, may cause thrombocytosis. Pernicious anemia caused by vitamin B₁₂ deficiency does not typically cause

thrombocytosis. However, correction of B₁₂ deficiency or folate deficiency may cause a “rebound”

thrombocytosis. Similarly, cessation of chronic ethanol use may also cause rebound thrombocytosis.

III-79. The answer is E. (Chap. 108) In a patient presenting with an elevated hemoglobin and hematocrit, the initial step in the evaluation is to determine whether erythrocytosis represents a true elevation in red blood cell (RBC) mass or whether spurious erythrocytosis is present because of plasma volume contraction. (See Figure III-79.) This step may be not necessary, however, in individuals with hemoglobin greater than 20 g/dL. After absolute erythrocytosis has been determined by

measurement of RBC mass and plasma volume, the cause of erythrocytosis must be determined. If there is not an obvious cause of the erythrocytosis, an erythropoietin level should be checked. An elevated erythropoietin level suggests hypoxia or autonomous production of erythropoietin as the cause of erythrocytosis. However, a normal erythropoietin level does not exclude hypoxia as a cause. A low erythropoietin level should be seen in the myeloproliferative disorder polycythemia vera (PV), the most likely cause of erythrocytosis in this patient. PV is often discovered incidentally when elevated hemoglobin is found during testing for other reasons. When symptoms are present, the most common complaints are related to hyper-viscosity of the blood and include vertigo, headache, tinnitus, and transient ischemic attacks. Patients may also complain of pruritus after showering. Erythromelalgia is the term give to the symptoms complex of burning, pain, and erythema in the extremities and is associated with thrombocytosis in P V. Isolated systolic hypertension and splenomegaly may be found. In addition to elevated red RBC mass and low erythropoietin levels, other laboratory findings in PV include thrombocytosis and leukocytosis with abnormal leukocytes present. Uric acid levels and leukocyte alkaline phosphatase may be elevated but are not diagnostic for P V. Approximately 30% of individuals with PV are homozygous for the JAK2 V617F mutation, and more than 90% are heterozygous for this mutation. This mutation located on the short arm of chromosome 9 causes constitutive activation of the Janus kinase (JAK) protein, a tyrosine kinase that renders erythrocytes resistant to apoptosis and allows them to continue production independently from erythropoietin. However, not every patient with PV expresses this mutation, and approximately 50% of patients with chronic myelofibrosis and essential thrombocytosis express this mutation. Thus, it is not recommended as an initial diagnostic test for PV but may be used for confirmatory purposes. Bone marrow biopsy provides no specific information in PV and is not recommended.

FIGURE III-79

III-80. The answer is C. (Chap. 109) This patient presents with typical findings of chronic myelogenous leukemia (CML), which has an incidence of 1.5 per 100,000 people yearly. The typical age of onset is in the mid-forties, and there is a slight male predominance. Half of individuals are asymptomatic at the time of diagnosis. If symptoms are present, they are typically nonspecific and include fatigue and weight loss. Occasionally, patients have symptoms related to splenic enlargement such as early satiety and left upper quadrant pain. Laboratory findings are suggestive of CML. A high leukocyte count of 100,000/μL is typical, with a predominant granulocytic differential, including neutrophils, myelocytes, metamyelocytes, and band forms. The circulating blast count should be less than 5%. Anemia and thrombocytosis are also common. The bone marrow demonstrates non-specific increase in cellularity with an increase in the myeloid-to-erythroid ratio. The diagnosis of CML is established by identifying a clonal expansion of a hematopoietic stem cell possessing a reciprocal translocation between chromosomes 9 and 22. This translocation results in the head-to-tail fusion of the breakpoint cluster region (BCR) gene on chromosome 22q11 with the ABL1 (named after the Abelson murine leukemia virus) gene located on chromosome 9q34. The bcr-abl fusion protein results in constitutive activation of abl tyrosine kinase enzyme that prevents apoptosis and leads to increased survival of the cells containing the mutation. Ultimately, untreated CML develops into an accelerated phase with increasing numbers of mutations and leads to acute blast crisis. The deletion of the long arm of chromosome 5 is present in some individuals with acute myeloid leukemias and is associated with older age at diagnosis. The inversion of chromosome 16 is typically present in acute myelomonocytic leukemia (M4 subtype). The translocation of the long arms of chromosomes 15 and 17 is the mutation associated with acute promyelocytic anemia that results in arrest of cellular differentiation that can be treated with pharmacologic doses of ATRA (all- trans retinoic acid). Finally, trisomy 12 is one of several mutations that may result in the development of chronic lymphocytic leukemia.

Date: 2016-04-22; view: 841