Atypical chronic myeloid leukemia

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Atypical chronic myeloid leukemia (aCML)[1] is a type of leukemia. It is a heterogeneous disorder belonging to the group of myelodysplastic/myeloproliferative (MDS/MPN) syndromes.

In aCML many clinical features (splenomegaly, myeloid predominance in the bone marrow with some dysplastic features but without a differentiation block) and laboratory abnormalities (myeloid proliferation, low leukocyte alkaline phosphatase values) suggest the diagnosis of chronic myelogenous leukemia (CML). However the lack of the pathognomonic Philadelphia chromosome[2] and of the resulting BCR-ABL1 fusion point to a different pathogenetic process. Since no specific recurrent genomic or karyotypic abnormalities have been identified in aCML, the molecular pathogenesis of this disease has remained elusive and the outcome dismal (median survival 37 months)[3] with no improvement over the last 20 years. This sharply contrasts with the outcome for CML, for which the prognosis was dramatically improved by the development of imatinib as a specific inhibitor of the BCR-ABL protein and in particular for CML.[4][5][6][7]

In 2012 SETBP1 was identified as a novel oncogene in aCML; specific somatic mutations of this gene were discovered in people with aCML and related diseases. These mutations, which are identical to the ones present in SGS as germline mutations, impair the degradation of SETBP1 and therefore cause increased cellular levels of the protein.[8]


  1. ^ Vardiman, J.W. et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 114, 937-51 (2009).
  2. ^ Nowell, P.C. & Hungerford, D.A. National Academy of Sciences. A minute Chromosome in Human Chronic Granulocytic Leukemia. Science 132, 1497-1497 (1960)
  3. ^ Kurzrock, R. et al. BCR rearrangement-negative chronic myelogenous leukemia revisited. J Clin Oncol. 19, 2915-26 (2001).
  4. ^ Druker, B.J. et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344, 1031-7 (2001).
  5. ^ Rebora, P. et al. Are chronic myeloid leukemia patients more at risk for second malignancies? A population-based study. Am J Epidemiol 172, 1028-33 (2010).
  6. ^ Gambacorti-Passerini, C. et al. Multicenter independent assessment of outcomes in chronic myeloid leukemia patients treated with imatinib. J Natl Cancer Inst. 103., 553-61 (2011).
  7. ^ Goldman, J.M. Chronic myeloid leukemia: a historical perspective. Semin Hematol 47, 302-11 (2010).
  8. ^ Piazza R, Valletta S, Winkelmann N, Redaelli S, Spinelli R, Pirola A, Antolini L, Mologni L, Donadoni C, Papaemmanuil E, Schnittger S, Kim DW, Boultwood J, Rossi F, Gaipa G, De Martini GP, di Celle PF, Jang HG, Fantin V, Bignell GR, Magistroni V, Haferlach T, Pogliani EM, Campbell PJ, Chase AJ, Tapper WJ, Cross NC, Gambacorti-Passerini C. Recurrent SETBP1 mutations in atypical chronic myeloid leukemia. Nat Genet. 2013 Jan;45(1):18-24. doi: 10.1038/ng.2495. Epub 2012 Dec 9.