The biology of CML blast crisis.

By B. Calabretta, D. Perrotti. Blood, 2004

649 citations recorded by the source corpus.

Chronic myelogenous leukemia (CML) evolves from a chronic phase characterized by the Philadelphia chromosome as the sole genetic abnormality into blast crisis, which is often associated with additional chromosomal and molecular secondary changes. Although the pathogenic effects of most CML blast crisis secondary changes are still poorly understood, ample evidence suggests that the phenotype of CML blast crisis cells (enhanced proliferation and survival, differentiation arrest) depends on cooperation of BCR/ABL with genes dysregulated during disease progression. Most genetic abnormalities of CML blast crisis have a direct or indirect effect on p53 or Rb (or both) gene activity, which are primarily required for cell proliferation and survival, but not differentiation. Thus, the differentiation arrest of CML blast crisis cells is a secondary consequence of these abnormalities or is caused by dysregulation of differentiation-regulatory genes (ie, C/EBPalpha). Validation of the critical role of certain secondary changes (ie, loss of p53 or C/EBPalpha function) in murine models of CML blast crisis and in in vitro assays of BCR/ABL transformation of human hematopoietic progenitors might lead to the development of novel therapies based on targeting BCR/ABL and inhibiting or restoring the gene activity gained or lost during disease progression (ie, p53 or C/EBPalpha).

Subfields: Genetics, Hematology

View Paper: https://www.semanticscholar.org/paper/4c28c1fecd576344a368409cdbc5288602f8c355

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In Genetics

1. C. Ashby
2. Hans Clevers
3. Zhesheng Chen
4. D. J. Barnes
5. J. Melo
6. R. Nusse
7. Pengfei Lu

In Hematology

1. C. Ashby
2. Hans Clevers
3. Zhesheng Chen
4. J. Melo

Citations in the corpus

• A Phase 2 Trial of Ponatinib in Philadelphia Chromosome–Positive Leukemias (2013, neutral): “Abdominal pain 74 (27) 20 (7) 15 (18) 4 (5) 6 (10) 1 (2) 6 (19) 2 (6)”
• Cancer stem cells: an evolving concept (2012, background): “Subsequent studies documented the acquisition of other cytogenetic alterations in emerging subclones that heralded the transition to blast crisis and thus implicated a number of genes in this transitio”
• Chronic myeloid leukaemia as a model of disease evolution in human cancer (2007, background): “However, the true relevance of BCR-ABL itself in causing disease progression is uncertai”
• The cancer stem cell: premises, promises and challenges (2011, background): “And the progression of CML into ALL blast crisis is caused by the emergence of subclones that harbor inactivating lesions in the cyclin-dependent kinase inhibitor 2A ( CDKN2A , also known as ARF ) gene in addition to the BCR-ABL1 translocatio”
• BCR-ABL tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: a review. (2010, background): “CR-ABL-mediated signaling is also associated with defective DNA epair, resulting in additional chromosomal alterations and mutaions, which may partly explain the aggressive nature of advanced ML [13].”