Genetic drivers in hematological malignancies are increasingly important in our understanding of cancer biology. Since the discovery of the philadelphia chromosome, gene fusions have been implicated as potential drug targets that are specific to tumor cells. Additionally, a large number of simple and complex mutations in oncogenes have been identified in recent years, making the number of relevant biomarkers in blood cancers quite large.

While cytogenetics, FISH, and array CGH have dramatically advanced our understanding of leukemia and lymphoma biology, the advent of next generation sequencing has enabled massively parallel analysis of multiple biomarkers in multiple samples at the same time, all while reducing batch size, turnaround time, and cost.

Archer® FusionPlex® and VariantPlex™ assays are purpose-built to identify key drivers in leukemia and lymphoma, enabling rapid identification of mutations for high-throughput laboratories.

Prevalence of Hematological Malignancies

Hematologic malignancies are cancers of the blood, lymph nodes and bone marrow. These cancers affect people of all age ranges, even children. According to the Leukemia and Lymphoma Society, 156,420 new blood cancer cases will be diagnosed, comprising 9.4% of the estimated 1,665,540 new cancer cases diagnosed in the US in 2014. Leukemia alone will account for 26% of cancers that develop in children ages 0-14. In the wider population, the highest incident rates per 100,000 people are for non-Hodgkin’s lymphoma at 19.7. Leukemia has the second highest incidence rate of 12.8. Myeloma, myelodysplastic syndrome, and Hodgkin’s lymphoma have incident rates of 5.9, 4.8 and 2.8, respectively (1). The 5-year survival rates vary by the type of blood cancer, but all have increased since 1960 and now range from 45% to 88% (2).

Types of Blood Cancers

Blood cancers are commonly categorized histologically as leukemia, lymphoma and myeloma. However, they can also be primarily characterized by cellular origin as myeloid neoplasms, lymphoid neoplasms and myeloproliferative disorders. Myeloid neoplasms affect the myeloid tissue—or all cells belonging to the granulocytic (neutrophil, eosinophil, basophil), monocytic/macrophage, erythroid, megakaryocytic and mast cell lineages (3). Common types of myeloid neoplasms include acute myeloid leukemia (AML) and chronic myelogeneous leukemia. Lymphoid neoplasms are derived from the clonal expansion and proliferation of B-T lymphocytes and NK cells and comprise acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL) (4). Myeloproliferative neoplasms occur when the bone marrow produces too many erythrocytes, thrombocytes or leukocytes (5). Types of myeloproliferative neoplasms include chronic myelogenous leukemia (CML), polycythemia vera, primary myelofibrosis, essential thyrocythemia, chronic neutrophilic leukemia and chronic eosinophilic leukemia.

New Cancer Cases

New cancer cases

Child Blood Cancers

Childhood blood cancer

Adolescent Blood Cancers

Adolescent boold cancers


Biologically and clinically distinct cancers can arise at each stage of normal hematopoietic differentiation. These cancers can be caused by a variety of mechanisms, including tumor suppressor gene inactivation, oncogene activation, and other genomic instabilities (6). In the vast majority of cases, a malignant cell develops one or more genetic mutations that stimulate unrestricted cellular proliferation. These cancer-driving genes are known as oncogenes (7). Aside from multiple random cytogenetic abnormalities, tumor-specific chromosomal translocations contribute directly to malignant transformation (6).

Researchers have developed targeted therapeutic strategies by exploiting specific chromosomal translocations. For example, the hallmark cause of CML is a reciprocal translocation between chromosome 9 and 22 (denoted as t(9;22)(q34;q11)) that results in a shortened chromosome 22—commonly known as the Philadelphia Chromosome (8). The molecular consequence of this translocation is a fusion between the breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (ABL1) genes (9). The BCR-ABL oncogene is translated into a 210kDa cytoplasmic fusion protein, p210BCR/ABL which is sufficient and essential for the malignant transformation of CML (10). p210BCR/ABL autophosphorylates resulting in constitutive tyrosine kinase activity tyrosine kinase activating numerous signal pathways. These pathways result in malignant transformation by interfering with regular cellular processes like apoptosis(11), adhesion (12) and cell proliferation and differentiation control (13,14). Subsequently, the multipotent hematopoietic stem cells clonally expand and leave the bone marrow prematurely. The premature cells differentiate in the blood and lead to the fatal acute phase (15). Unveiling this mechanism of action enabled researchers to develop a tyrosine kinase inhibitor (TKI) specific to the BCR-ABL protein. The TKI is a synthesized compound known as STI571 that, through competitive inhibition, prevents the phosphorylation of proteins involved in BCR-ABL signal transduction (16). The FDA approved the compound in 2001 as Imitinab—marketed by Novartis as Gleevec™. Given the therapeutic potential in targeted medicine, gene translocation identification is a recent focal point for blood cancer research.

Current Fusion Detection Methods in Research

Historically, researchers have used fluorescence in situ hybridization (FISH), immunohistochemistry (IHC) and reverse transcription polymerase chain reaction (RT-PCR) as the primary ways to detect gene fusions. Unfortunately, these approaches to molecular detection are limited in their multiplexing scalability and can be technically challenging to perform or interpret. Advances in next generation sequencing (NGS) provide researchers scalable and accurate gene fusion detection. Specifically, Anchored Multiplex PCR (AMP™) permits the simultaneous detection and identification of hundreds of target genes and their fusion partners using targeted NGS, even where a target’s fusion partners are unknown.

Gene fusions can be detected by histological and molecular methods, including IHC, FISH and RT-PCR (from left to right).

Gene fusions can be detected by histological and molecular methods, including IHC, FISH and RT-PCR (from left to right)

Blood Cancer Acronyms and References

Blood Cancer Acronymns

Anaplastic large cell lymphoma
Acute lymphoblastic leukemia/lymphoblastic lymphoma
Acute myeloid leukemia
Acute nonlymphoblastic leukemia
Acute promyelocytic leukemia
Biphenotypic leukemia
Classical hodgkin lymphoma
Chronic myeloproliferative disorder
Chronic myeloid Leukemia
Chronic neutrophilic leukemia
Diffuse large B-cell lymphoma
Myeloproliferative syndrome
Eosinophilia-associated atypical myeloproliferative neoplasms
Essential thrombocythemia
Follicular lymphoma
Hodgkin disease
Idiopathic hypereosinophilic syndrome
Juvenile myelomonocytic leukemia
Mature B-cell neoplasm
Myelodysplastic syndrome
Myloproliferative neoplasms
Peripheral T-cell lymphoma
Polycythemia vera
Refractory anemia with ringed sideroblasts
T-cell acute lymphoblastic leukemia


  1. American Cancer Society, Cancer Facts & Figures, 2014. Atlanta: American Cancer Society (2014).
  2. The Leukemia and Lymphoma Society. Facts & Statistics. (2014).
  3. J. W. Vardiman et al., The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: Rationale and important changes. Blood 114(5), 937–51 (2009).
  4. E. S. Jaffe, N. L. Harris, H. Stein, P. G. Isaacson, Classification of lymphoid neoplasms: the microscope as a tool for disease discovery Blood 112, 4384–4399 (2008)
  5. J. M. Klco et al., Molecular Pathology of Myeloproliferative Neoplasms. American Journal of Clinical Pathology 133, 602-615 (2010).
  6. F. Mitelman, B. Johansson, F. Mertens, The impact of translocations and gene fusions on cancer causation. Nat Rev Cancer 7, 233 (2007).
  7. B. Vogelstein et al., Cancer genome landscapes. Science 339, 1546–1558 (2013).
  8. P. C. Nowell, D. A. Hungerford, A minute chromosome in human chronic granulocytic leukemia. Science 132, 1497 (1960).
  9. R. Kurzrock et al., Philadelphia chromosome-positive leukemias: From basic mechanisms to molecular therapeutics. Annals of internal medicine 138(10), 819–830 (2003).
  10. S. Salesse et al., BCR/ABL: from molecular mechanisms of leukemia induction to treatment of chronic myelogenous leukemia. Oncogene 21, 8547-8559 (2002).
  11. G. Q. Daley et al., Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 247(4944), 824-30 (1990).
  12. D. Cortez et al., Structural and signaling requirements for BCR-ABL-mediated transformation and inhibition of apoptosis. Mol Cell Biol. 15(10), 5531-41 (1995).
  13. R. Bhatia et al., Role of abnormal integrin-cytoskeletal interactions in impaired beta1 integrin function in chronic myelogenous leukemia hematopoietic progenitors. Exp Hematol 29(9), 1384-96 (1997).
  14. L. Puil et al., Bcr-Abl oncoproteins bind directly to activatiors of the Ras signaling pathway. EMBO J. 13(4), 764-73 (1994).
  15. C. L. Sawyers, Molecular consequences of the BCR-ABL translocation in chronic myelogenous leukemia.Leuk Lymphoma 11(2), 101-3 (1993).
  16. B. J. Druker et al., Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344, 1031–1037 (2001).

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For Research Use Only. Not for use in diagnostic procedures. For Research Use Only. Not for use in diagnostic procedures.