General Characteristics of Leukocyte Neoplasms

Most malignancies of the hematopoietic system are acquired genetic diseases, which means that most patients are not born with the illness but acquire it sometime later. Most leukocyte malignancies are not localized but rather are systemic at the initiation of the malignant process. The bone marrow, in which the leukemias arise, and the lymphatic system, in which most lymphomas originate, access passages throughout the body. A single leukemia cell arising in the marrow can pass into the bloodstream and travel to any and all locations of the body. With rare exceptions, most treatments for leukocyte neoplasms given with curative intent are not localized, such as radiation or surgery, but must by nature be systemic-type treatments.

Etiology of Leukocyte Neoplasms

For most leukocyte neoplasms, causes directly related to the development of the malignancy are unknown. There are, however, a few exceptions. Environmental toxins can induce genetic changes, as discussed later in this chapter, leading to a malignancy phenotype. Environmental exposures known to lead to hematopoietic malignancies include radiation exposure, as experienced by survivors of atomic explosions, and exposure to organic solvents, such as benzene. There are two types of lymphoid malignancies in which viruses may play a pathogenetic role. The Epstein-Barr virus has been implicated as an etiologic factor in the development of Burkitt non-Hodgkin lymphoma. Similarly, human T-cell lymphotropic virus type 1 (HTLV-1) is the likely cause of adult T-cell leukemia/lymphoma. As discussed further in this chapter, there are some known familial cancer predisposition syndromes. In addition, as more cancer survivors live longer, it is clear that some alkylating agents and other forms of chemotherapy used to treat various forms of cancer can induce deoxyribonucleic acid (DNA) damage in hematopoietic cells, leading to hematologic malignancies.

Classification Schemes for Leukocyte Neoplasms

The French-American-British (FAB) classification of the acute leukemias was devised in the 1970s and 1980s. The FAB schemas were based largely on morphologic characteristics and relied heavily on examination of routine histologic stain preparations to distinguish lymphoid neoplasms from myeloid neoplasms (Figure 29-1). Although these types of diagnostic criteria have not been abandoned, pathologists are now moving toward more precise classification of many of the leukocyte neoplasms based on recurring chromosomal and genetic lesions found in many patients. These lesions are related to disruptions of oncogenes, tumor suppressor genes, and other regulatory elements that control proliferation, maturation, apoptosis, and other vital cell functions. In 2001 the World Health Organization (WHO) published new classification schemes for nearly all of the tumors of hematopoietic and lymphoid tissues.¹ In some cases WHO melded the older morphologic schemes with the newer schemes. For instance, in the WHO classification scheme for acute myeloid leukemias (AMLs) there are some remnants of the old FAB classification, but new classifications were introduced for leukemias associated with consistently recurring chromosomal translocations. This 2001 WHO classification of hematologic malignancies has undergone a recent revision.²

Chromosomal Abnormalities in Hematologic Neoplasms

In part because of the ease of access to bone marrow compared with other organs of the body, researchers have learned a great deal about the biology of cancer by studying hematopoietic neoplasms. The study of chromosomal translocations in hematologic malignancies has taught how a single mutation, or series of mutations in stepwise fashion, can lead to malignant transformation by disrupting the molecular machinery of the cell. The first two genetic lesions found in any kind of human cancer were identified as chromosomal translocations occurring in leukocyte malignancies. These were the t(9;22) translocation in chronic myelogenous leukemia (CML)³ and the t(8;14) translocation in Burkitt lymphoma.⁴

Oncogenes

Oncogenes originally were identified as genes that carried rapidly transforming retroviruses derived from normal cellular homologues, proto-oncogenes. The oncogene definition has evolved to specify genes that cause dominant-acting cancer mutations, regardless of whether they are derived from a retrovirus. The typical proto-oncogene codes for a protein involved in normal cell cycle regulation. Regulation proteins provide the signal transduction that carries messages about cell division and maturation (differentiation) from outside the cell to the nucleus. Mutations of these genes may form oncogenes that disrupt normal cell cycle processes.

Most chromosomal translocations in leukemias involve oncogenes. The “dominant” transforming oncogene is able to alter the gene product and transform the cell into a malignant phenotype, even in the presence of a residual normal allele. Even the afore-mentioned two examples, CML and Burkitt lymphoma, t(9;22) and t(8;14), involve oncogenes that are activated when brought into proximity with their new partners on fusion genes. In the case of CML, the ABL proto-oncogene on chromosome 9 is activated when fused to the BCR component of chromosome 22. In the case of Burkitt lymphoma, the MYC proto-oncogene on chromosome 8 is fused with the immunoglobulin heavy chain locus on chromosome 14. Although oncogenic transformation was first identified by karyotypic analyses, molecular biologic techniques have evolved rapidly over the last three decades, so that more genetic translocations are being identified that create novel fusion genes invisible at the cytogenetic level.

Tumor Suppressor Genes

Tumor suppressor genes are so named because they code for proteins that resist malignant transformation. These genes do not act in a dominant fashion as in the case of oncogenes; rather, cells are transformed into a malignant phenotype only after both alleles of these genes have been lost or otherwise inactivated, the so-called two-hit mechanism proposed by Knudson.⁵ Although tumor suppressor genes are harder to isolate and identify, numerous such genes have now been identified, and many have been found to be associated with autosomal dominant familial cancer predisposition syndromes. Some well-known examples include the RB1 tumor suppressor gene involved in familial retinoblastoma, the TP53 gene in Li-Fraumeni syndrome, the WT1 gene in Wilms tumor, and the NF1 gene in familial neurofibromatosis type 1. Perhaps more importantly, many of these tumor suppressor genes and their protein products are altered in many sporadic cancers, including hematologic cancers.

Other Genetic Changes

Beyond oncogenes and tumor suppressor genes, researchers have found genes that are involved in DNA repair mechanisms. Mutations in these genes do not lead to cellular transformation by altering signaling pathways, but rather lead to genetic instability and increased mutation rates. Examples of such genes are the DNA mismatch repair genes MLH1 and MSH2. Another example is the Fanconi anemia gene, FA, which is important for maintaining genomic stability in hematopoietic tissues.

Molecular Pathways Perturbed by Cellular Transformation

Regardless of the type of chromosomal or genetic abnormality, clinicians understand the molecular consequences that the formation of oncogenes or loss of tumor suppressor genes has on the proliferation and differentiation of hematologic tissues. Specialists recognize several mechanisms, including blocked differentiation, transcriptional repression, disruptions of cell signaling, progression, and apoptosis. The t(15;17) translocation found in acute promyelocytic leukemia (APL), which fuses the PML gene to the RARA (retinoic acid receptor alpha) gene, clearly results in a state of arrested differentiation, because RARA-induced differentiation is inhibited. Treating patients with APL with pharmacologically high doses of all-trans retinoic acid can overcome this block and permit APL cells to differentiate into normal neutrophils. In so doing, the APL cells lose their leukemic potential.

Other chromosomal abnormalities involve transcriptional repression of DNA and condensation abnormalities of chromatin, such as those involved in the core-binding factor leukemic subtypes of AML. A similar example on the lymphoid side of hematopoietic neoplasms are the chromosomal translocations involving the BCL6 gene. Normal BCL6 encodes for a transcriptional repressor responsible for recruiting the histone deacetylase complex, which regulates germinal center formation in lymph nodes. The mutation of BCL6 leads to overexpression of this normal protein so that DNA is excessively repressed, which in this case prevents lymphocytes from progressing beyond the germinal center stage of development.

Since the initial identification of the BCR/ABL fusion gene in CML, there are now many other examples of genetic abnormalities in myeloid malignancies in which the abnormality leads to disruption of cell signaling, often by way of activation of kinase cascades. FLT3 codes for a tyrosine kinase receptor preferentially expressed on hematopoietic stem cells that mediates proliferation and differentiation. A unique mutation resulting in an internal tandem duplication leads to constitutive activation of this pathway (i.e., always turned on) in many forms of AML and other hematopoietic malignancies. Other examples of gene mutations that alter kinase cascades in myeloid or lymphoid cells are c-KIT, NOTCH, JAK2, and RAS.

Many cyclin-dependent kinases are altered in lymphoid malignancies. The cyclin-dependent kinases tightly regulate cell cycle progression through the synthesis, proteolysis, and phosphorylation of cyclins.

Finally, another important molecular signaling pathway in cells involves programmed cell death, or apoptosis. This vital process allows organisms to eliminate redundant, damaged, aged, or infected cells. In the hematopoietic environment, apoptosis is essential to contain and control the massive expansion that the hematopoietic system is capable of generating at times of stress, infection, or hemorrhage. Caspases are a family of proteases that participate in the apoptotic cascade triggered in response to proapoptotic signals. The culmination of this apoptotic cascade is cellular disassembly. The BCL family contains many genes, some of which are proapoptotic and some of which are antiapoptotic. Many of the various forms of non-Hodgkin lymphoma seem to involve disruptions of BCL2, BCL6, BCL10, or other members of the caspase and BCL family of genes comprising the apoptotic cascade.

The list of chromosomal and molecular aberrations known to occur in the various leukocyte neoplasms continues to grow on an almost daily basis. Indexing this list is far beyond the scope of this chapter, but some condensed lists are provided in Chapter 31. More complete indices can be found in other publications such as the WHO reclassification scheme,¹ its 2008 revision, or other hematology textbooks.^6–10

Therapy for Leukocyte Neoplasms

The various forms of therapy available today for leukocyte neoplasms can be roughly divided into the following categories: chemotherapy, radiation therapy, supportive therapy, targeted therapy, and stem cell transplantation. In contrast to many solid tumors, numerous hematologic malignancies now have cure rates that are substantially higher than they were two or three decades ago. Many new and exciting therapies that are less toxic are now under development or are already employed in patient settings. These therapies are bringing more optimism to the care of patients with leukocyte neoplasms than ever before. Selection of the best therapy must start, however, with an accurate diagnosis. Even the most effective therapies do not work if they are applied in the wrong circumstances.

Curative treatment strategies are a realistic goal for patients with Hodgkin lymphoma, CML, hairy cell leukemia, and some forms of non-Hodgkin lymphoma, and for children with acute lymphoblastic leukemia.

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