Final Diagnosis -- Macrocytic anemia and thrombocytopenia




Patients with Downs syndrome have approximately a 1/100 incidence of Acute myelogenous leukemia (AML) with a relative risk of 10-20 fold as compared to cytogenetically normal individuals (1,4). The majority of these patients >50% have acute megakaryoblastic leukemia (AMKL), which represents a 46 fold increase in relative risk.

Transient myeloproliferative disorder (TMD) is a unique, neoplasia specific to Down's syndrome (DS). It affects approximately 10%of DS neonates. In 20-30% of cases, it reoccurs as progressive acute megakaryoblastic leukemia (AMKL) at 2-4 years of age. Morphologically the blasts of TMD and AMKL can appear identical. Immunophenotypically, the cells have similar profile (2,3,4,5). The blasts are usually CD 45, CD 34, CD 117,CD 38, CD 33 positive. Furthermore, CD61 and CD41 used to differentiate megakaryocytic lineage may be positive in both. Given the transient nature of TMD versus the potential lethal nature of AMKL, there is an important distinction to be made.

The exact nature of molecular events in both AMKL and TMD are unknown, however it is believed that mutations in the GATA1 gene are a key event. GATA1 is a transcription factor located on the X chromosome involved in the maturation of erythroid and megakaryocyte lines (2,3). However, mutations are non- specific and found in both. Therefore, they cannot be used in differentiating on from the other. Interestingly enough though, identical mutations of GATA can be found in TMD's and AMKL's which subsequently evolve from them. This suggests a clonal evolution of some TMD's to delayed AMKL's, but differences in early AMKL's and TMD's.

Currently, there are some efforts under way using microarray technology to differentiate early AMKL and TMD's (1). One recent study showed a significant increase in the amount of CDKN2C in AMKL but not TMD. This of interest since CDKN2C is a negative effector of GATA and an increased quantity my point to a loss of GATA inhibition in AMKL. There was an inverse correlation with levels of MYCN (neuroblastoma protooncogene). The latter was more abundant in TMD. MYCN belongs to the myc family of oncogenes. It is seen in 25% of neuroblastomas. Lastly, there is an increased expression of preferentially expressed in melanoma gene (PRAME) in AMKL but not TMD (1,6). This might make it a good candidate for differentiating the two.

It should be noted, however that none of these strategies differentiate between TMD which progress to delayed AMKL's and those that do not. Nor do they differentiate between TMD and non AMKL leukemia. Ultimately, the only way to differentiate the two is to watch and observe the patient for several weeks


  1. Suzanne McElwaine, Claire Mulligan, Jurgen Groet, Monica Spinelli, Andrea Rinaldi, Gareth Denyer and Afua Mensah, Microarray transcript profiling distinguishes the transient from the acute type of megakaryoblastic leukaemia (M7) in Down's syndrome, revealing PRAME as a specific discriminating marker, British Journal of Haematology, 125, 729-742
  2. Gamis, A.S. & Hilden, J.M. (2002) Transient myeloproliferative disorder, a disorder with too few data and many unanswered questions: does it contain an important piece of the puzzle to understanding hematopoiesis and acute myelogenous leukemia? Journal of Pediatric Hematology/Oncology, 24, 2-5.
  3. Groet, J., McElwaine, S., Spinelli, M., Rinaldi, A., Burtscher, I., Mulligan, C., Mensah, A., Cavani, S., Dagna-Bricarelli, F., Basso, G., Cotter, F.E. & Nizetic, D. (2003) Acquired mutations in GATA1 in neonates with Down's syndrome with transient myeloid disorder. Lancet, 361, 1617-1620.
  4. Hitzler, J.K., Cheung, J., Li, Y., Scherer, S.W. & Zipursky, A. (2003) GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome. Blood, 101, 4301-4304.
  5. Homans, A.C., Verissimo, A.M. & Vlacha, V. (1993) Transient abnormal myelopoiesis of infancy associated with trisomy 21. American Journal of Pediatric Hematology and Oncology, 15, 392-399.
  6. Ikeda, H., Lethe, B., Lehmann, F., van Baren, N., Baurain, J.F., de Smet, C., Chambost, H., Vitale, M., Moretta, A., Boon, T. & Coulie, P.G. (1997) Characterization of an antigen that is recognized on a melanoma showing partial HLA loss by CTL expressing an NK inhibitory receptor. Immunity, 6, 199-208.
  7. Karandikar, N.J., Aquino, D.B., McKenna, R.W. & Kroft, S.H. (2001) Transient myeloproliferative disorder and acute myeloid leukemia in Down syndrome. An immunophenotypic analysis. American Journal of Clinical Pathology, 116, 204-210.
  8. Mundschau, G., Gurbuxani, S., Gamis, A.S., Greene, M.E., Arceci, R.J. & Crispino, J.D. (2003) Mutagenesis of GATA1 is an initiating event in Down syndrome leukemogenesis. Blood, 101, 4298-4300.

Contributed by Raj N Hari, MD, and Sandra S Kaplan, MD

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