• common in hematologic malignancy; uncommon in solid tumors
• often (not always) reciprocal, but one of the new fusion genes predominates

• are growth regulatory genes which if abnormally expressed or altered contribute to the pathogenesis of cancer cells.
• Some examples include: Growth factors and receptors (Erb-B2, IL-3, TCR), cell-cycle regulators (p53, p21, p27, p16, Rb, cyclin D, ATM), transcription factors (myc, jun, tal (ALL), creb, p53), DNA repair (Mlh1, Msh2, Xpa-G, Blooms); Membrane bound (Ras, SRC); and nuclear membrane Þ Apoptosis (Bcl2).
• Oncogenes in Hematologic Malignancies:
• C-myc overexpression and amplification seen in Burkitt’s lymphoma.
• p53 mutation can be seen in AML, as well as in intermediate and high grade lymphomas.

Reciprocal Translocations – cause many hematological malignancies!

• Chronic Myelogenous Leukemia/Acute Lymphocytic Leukemia
• t(9;22): Philadelphia chromosome – ABL gene on chromosome 9 is translocated to BCR gene on chromosome 22 (c-ABL encodes P145 protein which has weak tyrosine kinase activity, however BCR/ABL hybrid has enhanced tyrosine kinase activity) Þ Ý tyrosine kinase Þ nuclear transcriptional (via Stat 1,5, myc, ras, PI-3k).
• BCR/ABL – longer chimeric protein (p210) Þ Chronic Myelogenous Leukemia; if shortened, chimeric protein (p190) Þ Acute Lymphocytic Leukemia (higher kinase activity), acute presentation.
• CML – chronic phase can last 1-5yrs., accelerated phase – 6 months, and a blast crisis 3 weeks. Myeloid proliferation is present.
• ALL – acute presentation, lymphoblasts present, CNS involvement, and poor prognosis.
• Acute Promyelocytic Leukemia (APL)
• Proliferation of promyelocytes in bone marrow and peripheral blood
• Disseminated Intravascular Coagulation Þ most common cause of death
• Unique karotypic marker t[15;17] [q22;q11-12]
• Links PML gene on 15 to RAR (retinoic acid) on 17 – a regulator of transcriptional activation
• Protein expressed is much more resistant to retinoic acid Þ blocks maturation of myelocytes due to ß sensitivity to retinoic acid, however, can be overcome by increased amounts of retinoic acid. In tissue culture, retinoic acid can induce APL cells to differentiate into granulocytes Þ trans-retinoic acid can cause remission of APL.
• Core Binding Factor (CBF) Leukemias
• CBF is a transcription factor complex expressed in hematopoietic cells
• Translocations of the CBF gene result in increased translocations within the genes
• Heterodimer transcription unit made of alpha and beta portions. Alpha binds to the DNA and beta is responsible for differentiation signaling.
• CBF = AML1, alpha domain gene
• t(8;21) Þ Acute Myelogenous Leukemia, due to fusion of AML1/ETO genes
• t(12;21) Þ Acute Lymphoblastic Leukemia, due to fusion of TEL/AML1
• t(2;21) Þ Myelodysplastic Syndrome, Chronic Myelogenous Leukemia; due to fusion of AML1/EV1
• inv (16) Þ AML , due to inversion of CBFbeta/MYH11; has a good prognosis with a high eosinophilic presentation.
• Associated with good prognosis – chemosensitivity, do not bone marrow transplant while in 1^st remission
• The fusion gene can be detected by PCR in remission [poorer prognosis].
• Burkitt’s Lymphoma
• C-myc (8) translocated to
• Heavy chain (14); t(8;14) Þ Ý c-myc
• Light chain (22); t(8;22) Þ Ý c-myc
• Myc expression in B cells blocks differentiation, clonal extinction, and prevents apoptosis.
• Transformation is associated with EBV virus
• B-Cell Lymphoma
• t(14;18) – BCL2 is translocated to heavy chain (chromosome 14) Þ Ý expression of BCL2.
• Ca²⁺ influx (important) in the mitochondria is controlled by BCL2. Bax (another protein) can come in and be proapoptotic (Bax Þ cytochrome c Þ caspase 3 Þ caspase 9 Þ apoptosis); however, BCL2 is anti-apoptotic by sequestering Bax and stopping the cell from apoptosis. Therefore, Ý BCL2 Þ no apoptosis of B-cells Þ lymphoma.
• Expansion of the lymphocyte pool by BCL2 allows for further genetic aberration to occur Þ lymphoma.
• Decreases steroid and chemotherapy induced apoptosis, as well.
• The c-myc oncogene can cooperate with Bcl-2 in promoting tumorigenesis. t(14;18) Þ B cell expansion Þ follicular B-cell lymphoma Þ c-myc amplification, p53 mutation Þ large cell lymphoma
• Evidence that fusion genes cause hematologic malignancies – as seen in transgenic mice
• BCR-ABL Þ myeloproliferative syndrome
• Hc-BCL2 Þ lymphoproliferative syndrome
• RAR-PML Þ PML
• PCR has improved our prognosis of cancers since the translocations can be identified and characteristics of the translocation can be accurately assessed.