Chronic myeloid leukemia: reminiscences and dreams

Abstract

With the deaths of Janet Rowley and John Goldman in December 2013, the world lost two pioneers in the field of chronic myeloid leukemia. In 1973, Janet Rowley, unraveled the cytogenetic anatomy of the Philadelphia chromosome, which subsequently led to the identification of the BCR-ABL1 fusion gene and its principal pathogenetic role in the development of chronic myeloid leukemia. This work was also of major importance to support the idea that cytogenetic changes were drivers of leukemogenesis. John Goldman originally made seminal contributions to the use of autologous and allogeneic stem cell transplantation from the late 1970s onwards. Then, in collaboration with Brian Druker, he led efforts to develop ABL1 tyrosine kinase inhibitors for the treatment of patients with chronic myeloid leukemia in the late 1990s. He also led the global efforts to develop and harmonize methodology for molecular monitoring, and was an indefatigable organizer of international conferences. These conferences brought together clinicians and scientists, and accelerated the adoption of new therapies. The abundance of praise, tributes and testimonies expressed by many serve to illustrate the indelible impressions these two passionate and affable scholars made on so many people's lives. This tribute provides an outline of the remarkable story of chronic myeloid leukemia, and in writing it, it is clear that the historical triumph of biomedical science over this leukemia cannot be considered without appreciating the work of both Janet Rowley and John Goldman.

Figure 1.

Survival with chronic myeloid leukemia over time (1993–2013): the German CML-Study Group experience. Courtesy of Prof H Kantarjian; adapted, with permission, from Harrison’s Principles of Internal Medicine, 2014.

Janet Rowley and John Goldman.

Figure 2.

Milestones in the study and treatment of chronic myeloid leukemia.

Figure 3.

Detection of the t(9;22)(q34;q11) chromosomal translocation. (A) Karyotype from a patient with chronic myeloid leukemia depicting the translocation, t(9;22)(q34;q11) (abnormal chromosomes arrowed). (B) A partial karyotype of the same chromosomes 9 and 22 with the relevant FISH probes for BCR and ABL1 is shown. The red green fusion signals of the BCR-ABL1 and ABL1-BCR on chromosomes 22 and 9, respectively, are also shown. A metaphase counterstained with DAPI (blue) indicates their appearance under the fluorescent microscope (C).

Figure 4.

The structure of the normal BCR and ABL1 genes and the fusion transcripts found in Ph-positive leukemias. The ABL1 gene contains two alternative 5′ exons (named 1b and 1a) followed by 10 ‘common’ exons numbered a2–a11 (green boxes). Breakpoints in CML and Ph-positive ALL usually occur in the introns between exons 1b and 1a or between exons 1a and a2 (as shown by vertical arrows). The BCR gene comprises a total of 23 exons, 11 exons upstream of the M-BCR region, five exons in the M-BCR that were originally termed b1–b5 and now renamed e12–e16, and seven exons downstream of M-BCR (orange boxes). For convenience, only exons e1, e12–e16 and e23 are shown. Breakpoints in CML usually occur between exons e13 (b2) and e14 (b3) or between exons e14 (b3) and e15 (b4) of the M-BCR (as shown by two vertical arrows placed centrally). The majority of patients with Ph-positive ALL have breakpoints in the first intron of the gene, between e1 and e2 (arrow at left). Three possible BCR–ABL1 mRNA transcripts are shown below. The first two (e13a2 and e14a2, respectively) are characteristic of CML. The bottom mRNA (e1a2) is found in the majority of patients with Ph-positive ALL.

Figure 5.

Cytoplasmic BCR-ABL1 activates a myriad of signal pathways. BCR-ABL1 domain structure and simplified representation of molecular signaling pathways activated in chronic myeloid leukemia (CML) cells. Following dimerization of BCR-ABL1, autophosphorylation generates docking sites on BCR-ABL1 that facilitate interaction with intermediary adapter proteins (brown) such as GRB2. CRKL and CBL are also direct substrates of BCR-ABL1 that are part of a multimeric complex. These BCR-ABL1-dependent signaling complexes in turn lead to activation of multiple pathways whose net result is enhanced survival, inhibition of apoptosis, and perturbation of cell adhesion and migration. A subset of these pathways and their constituent transcription factors (blue), serine/threonine-specific kinases (purple), cell cycle regulatory protein (yellow) and apoptosis-related proteins (red) are shown. Also included are a few pathways that have been more recently implicated in CML stem cell maintenance and BCR-ABL1-mediated disease transformation (orange). However, it is important to note that this is a simplified diagram and that many more associations between BCR-ABL and signaling proteins have been reported.

Figure 6.

Imatinib binds an Inactive ABL1 conformation. Adapted, with permission, from Schindler et al. Science 2000.

Figure 7.

Mutations in the kinase domain of ABL1 identified in tyrosine kinase inhibitors (TKI) resistant chronic myeloid leukemia cells. The 10 most frequent mutations, accounting for approximately 70% of TKI-resistant CML patients are highlighted in red.

Figure 8.

Chemical structures of imatinib, nilotinib, dasatinib, bosutinib and ponatinib.

Figure 9.

Chronic myeloid leukemia survival after allo-stem cell transplantation. Data from the Fred Hutchinson Cancer Research Center, Seattle. *Includes both matched related and unrelated donors. Patients receiving allografts at the Fred Hutchinson Cancer Research Center from 1995 to the present. Figure is courtesy of Dr Ted Gooley. SCT: stem cell treatment.

Figure 10.

Targeting chronic myeloid leukemia cells at different levels.