Article | Published:

Clinical, immunophenotypic, and genomic findings of acute undifferentiated leukemia and comparison to acute myeloid leukemia with minimal differentiation: a study from the bone marrow pathology group


Acute undifferentiated leukemia is a rare type of acute leukemia that shows no evidence of differentiation along any lineage. Clinical, immunophenotypic and genetic data is limited and it is uncertain if acute undifferentiated leukemia is biologically distinct from acute myeloid leukemia with minimal differentiation, which also shows limited myeloid marker expression and has been reported to have a poor prognosis. We identified 92 cases initially diagnosed as acute undifferentiated leukemia or acute myeloid leukemia with minimal differentiation from pathology databases of nine academic institutions with available diagnostic flow cytometric data, cytogenetic findings, mutational and clinical data. Outcome analysis was performed using Kaplan Meier test for the 53 patients who received induction chemotherapy. Based on cytogenetic abnormalities (N = 30) or history of myelodysplastic syndrome (N = 2), 32 cases were re-classified as acute myeloid leukemia with myelodysplasia related changes. The remaining 24 acute undifferentiated leukemia patients presented with similar age, blood counts, bone marrow cellularity, and blast percentage as the remaining 30 acute myeloid leukemia with minimal differentiation patients. Compared to acute myeloid leukemia with minimal differentiation, acute undifferentiated leukemia cases were characterized by more frequent mutations in PHF6 (5/15 vs 0/19, p = 0.016) and more frequent expression of TdT on blasts (p = 0.003) while acute myeloid leukemia with minimal differentiation cases had more frequent CD123 expression (p = 0.042). Outcome data showed no difference in overall survival, relapse free survival, or rates of complete remission between acute undifferentiated leukemia and acute myeloid leukemia with minimal differentiation groups (p > 0.05). Acute myeloid leukemia with myelodysplasia-related changes patients showed shorter survival when censoring for bone marrow transplant as compared to acute undifferentiated leukemia (p = 0.03) and acute myeloid leukemia with minimal differentiation (p = 0.002). In this largest series to date, the acute undifferentiated leukemia group shows distinct characteristics from acute myeloid leukemia with minimal differentiation, including more frequent PHF6 mutations and expression of TdT.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    Weinberg OK, Arber DA. Mixed-phenotype acute leukemia: historical overview and a new definition. Leukemia. 2010;24:1844–51.

  2. 2.

    Borowitz MJ, Bene MC, Harris NL, et al. Acute leukemias of ambiguous lineage. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, (Eds). WHO classification of tumours of haematopoietic and lymphoid tissues.. Lyon: IARC Press; 2008. p. 150–5.

  3. 3.

    Cuneo A, Ferrant A, Michaux JL, et al. Cytogenetic and clinicobiological features of acute leukemia with stem cell phenotype: study of nine cases. Cancer Genet Cytogenet. 1996;92:31–6.

  4. 4.

    Heesch S, Neumann M, Schwartz S, et al. Acute leukemias of ambiguous lineage in adults: molecular and clinical characterization. Ann Hematol. 2013;92:747–58.

  5. 5.

    Kurosawa S, Toya T, Kishida Y, et al. Outcome of patients with acute undifferentiated leukemia after allogeneic hematopoietic stem cell transplantation. Leuk Lymphoma. 2018;4:1–4.

  6. 6.

    Bennett JM, Catovsky D, Daniel MT, et al. Proposal for the recognition of minimally differentiated acute myeloid leukaemia (acute myeloid leukemia-MO). Br J Haematol. 1991;78:325–9.

  7. 7.

    Amadori S, Venditti A, Del Poeta G, et al. Minimally differentiated acute myeloid leukemia (acute myeloid leukemia-M0): a distinct clinico-biologic entity with poor prognosis. Ann Hematol. 1996;72:208–15.

  8. 8.

    Venditti A, Del Poeta G, Stasi R, et al. Biological profile of 23 cases of minimally differentiated acute myeloid leukemia (Acute myeloid leukemia-M0) and its clinical implications. Blood. 1996;87:418–20.

  9. 9.

    Béné MC, Bernier M, Casasnovas RO, et al. Acute myeloid leukaemia M0: haematological, immunophenotypic and cytogenetic characteristics and their prognostic significance: an analysis in 241 patients. Br J Haematol. 2001;113:737–45.

  10. 10.

    Arber DA, Brunning RD, Orazi A, et al. Acute myeloid leukemia, Not otherwise specified. In: Swerdlow SH, Campo E, Harris NL, et al. editors. WHO classification of tumours of haematopoietic and lymphoid tissues. Revised. 4th edition. Lyon, France: International Agency for Research on Cancer; 2017. p. 156–66.

  11. 11.

    Kao HW, Liang DC, Wu JH, et al. Gene mutation patterns in patients with minimally differentiated acute myeloid leukemia. Neoplasia. 2014;16:481–8.

  12. 12.

    Silva FP, Swagemakers SM, Erpelinck-Verschueren C, et al. Gene expression profiling of minimally differentiated acute myeloid leukemia: M0 is a distinct entity subdivided by RUNX1 mutation status. Blood. 2009;114:3001–7.

  13. 13.

    Arber DA, Orazi A, Hasserjian R, et al. The2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405.

  14. 14.

    Lancet JE, Uy GL, Cortes JE, et al. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol. 2018;36:2684–92.

  15. 15.

    Weinberg OK, Pozdnyakova O, Campigotto F, et al. Reproducibility and prognostic significance of morphologic dysplasia in de novo acute myeloid leukemia. Mod Pathol. 2015;28:965–76.

  16. 16.

    ISCN. An international system for human cytogenomic nomenclature. Basel; New York: Karger; 2016.

  17. 17.

    Quesada AE, Hu Z, Routbort MJ, et al. Mixed phenotype acute leukemia contains heterogeneous genetic mutations by next-generation sequencing. Oncotarget. 2018;9:8441–9.

  18. 18.

    Cheson BD, Cassileth PA, Head DR, et al. Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol.. 1990;8:813–9.

  19. 19.

    Wolach O, Stone RM. How I treat mixed-phenotype acute leukemia. Blood. 2015;125:2477–85.

  20. 20.

    Gaidzik VI, Teleanu V, Papaemmanuil E, et al. RUNX1 mutations in acute myeloid leukemia are associated with distinct clinico-pathologic and genetic features. Leukemia. 2016;30:2160–8.

  21. 21.

    Mrózek K. Cytogenetic, molecular genetic, and clinical characteristics of acute myeloid leukemia with a complex karyotype. Semin Oncol. 2008;35:365–77.

  22. 22.

    Haferlach C, Dicker F, Herholz H, et al. Mutations of the TP53 gene in acute myeloid leukemia are strongly associated with a complex aberrant karyotype. Leukemia. 2008;22:1539–41.

  23. 23.

    Bowen D, Groves MJ, Burnett AK, et al. TP53 gene mutation is frequent in patients with acute myeloid leukemia and complex karyotype, and is associated with very poor prognosis. Leukemia. 2009;23:203–6.

  24. 24.

    Ohgami RS, Ma L, Merker JD, et al. Next-generation sequencing of acute myeloid leukemia identifies the significance of TP53, U2AF1, ASXL1, and TET2 mutations. Mod Pathol. 2015;28:706–14.

  25. 25.

    Stölzel F, Mohr B, Kramer M, et al. Karyotype complexity and prognosis in acute myeloid leukemia. Blood Cancer J. 2016;6:e386.

  26. 26.

    Van Vlierberghe P, Palomero T, Khiabanian H, et al. PHF6 mutations in T-cell acute lymphoblastic leukemia. Nat Genet. 2010;42:338–42.

  27. 27.

    Van Vlierberghe P, Patel J, Abdel-Wahab O, et al. PHF6 mutations in adult acute myeloid leukemia. Leukemia.. 2011;25:130–4.

  28. 28.

    Mi X, Griffin G, Lee W, et al. Genomic and clinical characterization of B/T mixed phenotype acute leukemia reveals recurrent features and T-ALL like mutations. Am J Hematol. 2018;93:1358–67.

  29. 29.

    Soto-Feliciano YM, Bartlebaugh JME, Liu Y, et al. PHF6 regulates phenotypic plasticity through chromatin organization within lineage-specific genes. Genes Dev. 2017;31:973–89.

  30. 30.

    Lindsley RC, Mar BG, Mazzola E, et al. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood. 2015;125:1367–76.

  31. 31.

    Gelsi-Boyer V, Brecqueville M, et al. Mutations in ASXL1 are associated with poor prognosis across the spectrum of malignant myeloid diseases. J Hematol Oncol. 2012;5:12–14.

  32. 32.

    Grossmann V, Tiacci E, Holmes AB, et al. Whole-exome sequencing identifies somatic mutations of BCOR in acute myeloid leukemia with normal karyotype. Blood. 2011;118:6153–63.

  33. 33.

    Sood R, Kamikubo Y, Liu P. Role of RUNX1 in hematological malignancies. Blood. 2017;129:2070–82.

  34. 34.

    Ding LW, Sun QY, Tan KT, et al. Mutational landscape of pediatric acute lymphoblastic leukemia. Cancer Res. 2017;77:390–400.

Download references

Author information

Conflict of interest

The authors declare that they have no conflict of interest.

Correspondence to Olga K. Weinberg.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark
Fig. 1
Fig. 2