Chromosome Abnormalities and Their molecular Correlates in Acute Leukemia SALJUAN CHEN State Key laboratory of medical genomics Shanghai Institute of Hematology, Ruijin Hospital Shanghai Second Medical University(SsMU)
Chromosome Abnormalities and Their Molecular Correlates in Acute Leukemia SAI-JUAN CHEN State Key Laboratory of Medical Genomics Shanghai Institute of Hematology, Ruijin Hospital Shanghai Second Medical University(SSMU)
Development of Classification of Acute Leukemia 1976 French-American-British(FAB) Cooperative Group proposed classification of acute leukemia based on morphologic criteria that were subsequently refined in 1981 and 1985 1986 Morphologic, immunologic and cytogenetic (MIC) classification was introduced. Recognition of importance of cytogenetics in the diagnosis and treatment of acute leukemia 2001 World Health Organization(WHO) classification recognized new clinically relevant molecular genetic lesions
Development of Classification of Acute Leukemia 1976 French-American-British (FAB) Cooperative Group proposed classification of acute leukemia based on morphologic criteria that were subsequently refined in 1981 and 1985 1986 Morphologic, immunologic and cytogenetic (MIC) classification was introduced. Recognition of importance of cytogenetics in the diagnosis and treatment of acute leukemia 2001 World Health Organization (WHO) classification recognized new clinically relevant molecular genetic lesions
World Health Organization(WHO)Classification of Acute Leukemia with Corresponding FAB Classification Subtypes WHO classification" C ore esponding FAB subtypes Precursor lymphoblastic leukemia/lymphoblastic lymphoma Precursor B-cell acute lymphoblastic leukemia/lymphoma LI L2 Precursor T-lymphoblastic leukemia/lymphoblastic lymphoma LI L2 Burkitts lymphoma/leukemia Endemic Burkitt's lymphoma/leukemia Sporadic Burkitt's lymphoma/leukemia Immunodeficiency-associated Burkitt's lymphoma/leukemia 3 AML with recurrent genetic abnormalities AML with t(8: 21)( 22: 22): AMLl-ETO M2>MI>M4>MO AML wth abnormal marrow eosinophilia and inv(16)(p1 3q22)or t(16: 16)(p13: q22): CBFB-MYHll M4Eo>M4>M2>MI Acute promyelocytic leukemia with t(15: 17)(q22: q 12): PML-RARa M3>M2>MI AML with 11q23 abnormalities: MLL rearrangements M5>M4>M2>MI>MO AML with multilineage dysplasia Following a myelodysplastic syndrome or myeloproliferative disorder or without antecedent myelodysplastic syndrome M2>M4>M6 AML and myelodysplastic syndrome, therapy related Alkylating agent-related M2>M4>M6 Topoisomerase type II inhibitor-related M5>M4>M2>MI Other types AML not otherwise categorized Acute myeloid leukemia minimally differentiated Acute myeloid leukemia without maturation MI Acute myeloid leukemia with maturation M2 Acute myelomonocytic leukemia M4 Acute monoblastic leukemia 15 Acute erythroid leukemia Acute megakaryoblastic leukemia M7 Acute basophilic leukemia Acute panmyelosis with myelofibrosis M7:?MI: MDS Myeloid sarcoma Abbreviations: FAB, French-American-British: MDS, myelodysplastic syndrome. aFor details. see ref 6 bFor details, see refs. 3 and 4
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Acute leukemia of ambiguous lineage Undifferentiated acute leukemia CHLA-DR, CD34, CD38) Bilineal acute leukemia (dual population of blasts) Biphenotypic acute leukemia co-expression of myeloid and other lineage antigen)
Acute leukemia of ambiguous lineage • Undifferentiated acute leukemia (HLA-DR, CD34, CD38) • Bilineal acute leukemia (dual population of blasts) • Biphenotypic acute leukemia (co-expression of myeloid and other lineage antigen)
Major differences between WHO and FAB Replacing the morphologic terms of LI and L2 ALL with an immunologic classification consisting of precursor-B and precursor- t lymphoblastic leukemias that are further subgrouped by cytogenetic abnormalities Grouping L3 ALL with Burkitts lymphoma Lowering the blast count from 30 to 20% for the diagnosis of AML, with elimination of the myelodysplastic subgroup of refractory anemia with excess blasts in transformation RAEB-IT) Revision of the mds subdivision based on number of dysplastic lineages, presence of ringed sideroblasts, and blast percentage Recognition of distinct cytogenetic AML subtypes New category of AMl with multilineage dysplasia with or without an antecedent mds New category of Therapy-Related AML New category of Acute Leukemia of Ambiguous lineage Inclusion of a pure erythroid leukemia(M6b)in the AML Not Otherwise Categorized subgroup Recognition of the rare acute basophilic leukemia also in the AML Not Otherwise Categorized subgroup
Major differences between WHO and FAB
Cytogenetic Classification of Acute Lymphoblastic Leukemia(ALL) Karyon Genes involved Leukemia subtype Clinical prognosis Hyperdiploid >50 Early pre- B-or pre-B-ALL Favorable (12: 21)(p12: q 22) TEL, AMLI Early pre-B-or pre- B-ALL Favorable tl:19)g23:13)PBx,E2A Pre-B-ALL Good with intensified therapy 18.)24. c-MYC-b Mature B-ALL (ALL-L3) Favorable without central nervous system disease t19)9g23:133) MLL, ENI Early pre-B-or T-ALL Poor in patients 10 yr of age (9: 22)(934: q l1) ABL, BCR Early pre- B-or pre-B-ALL Poor Near haploid <30 Early pre-B-ALL oor chromosomes iNcludes t(8:: 14)(q24: q32), t(2: 8)(p 12: g 24), and t 48: 22)(24: q1 1)where heavy, K, and immunoglobulin genes are involved on chromosomes 14, 2 and 22 respectively
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Cytogenetic Classifications of Acute Myeloid Leukemia Group CALGB(96) MRC(97,98,100) GAMLCG(101) SWOG (99) Favorable t(15;17) t(15: 17)with any abnormality t(15;17) t(15: 17) with any abnormality inv(16/(16;16/del(16)inv(16/t(16;16/del(16q) inv(16/(16;16) invl6/(16;16del(16q) with any other abnormality with any other abnormality t(8;21) t(8: 21) with any other abnormality t(8: 21) t(8: 21) without del(9q)or Intermediate Normal karyotype Normal karyotype Normal karyotype Normal karyotype +8,-Y,+6,der(12p) Other abnormalities +8, -Y, +6, der(12p) 1 1q23 abnormality del(9q) or del(7q) without other abnormality Complex karyotype (23 but <5 abnormalities) All abnormalities of unknown prognostic significance Unfavorable Other abnormalities -5/del(5q)-7 5/del(5q).-7/del(7q)-5/del(5q).-7/del(7q nv(3q), del(9q), 17p abnormality inv(3), 17p nv(3),17pabn,20q,+13, t(9;22) t(9;22) I 1g23 1 1q23 abnormality (8: 21)with del(9q) complex karyotype Complex karyotypes with Complex karyotype Complex karyotypes with ≥5 abnormalities 3 abnormalities Unknown All other clonal karyotypes with <3 chromosomal abnormalities Abbreviations: CALGB, Cancer and Leukemia Group B: MRC, Medical research Council; SWOG, Southwestern Oncology Group; GAMLCG German AML Cooperative Group
白血病染色体易位 ALL AML 30% AMLt电 t821) 12% MYc BCR-ABL 7q35TCRB P98-HQXA9 14011/TCRao MYC /29 CBFD-MYH11 t8;14)t(28)822) inv(18) 1% FUS-ERG 20% MLL-AF9 E2A-PBX1 TELAML1 1%t1621) t81) t(1: 19) E2A-HLF t12:21 PML-RARa DEK-CAN 图7v) MLL fusio t17:10)t:111:11+41 t15;17)t1:17 NPM-MLF1 t5:17) Bcel Pro-B cell 口 Promyelocytic口 Myelodysplastic, diverse myel Most of the fusion genes involved in AL translocations are transcription factors(TFs): abnormalities in lineage commitment and differentiation Look AT Science. 278: 1059
Look AT. Science, 278: 1059 白血病染色体易位 Most of the fusion genes involved in AL translocations are transcription factors (TFs): abnormalities in lineage commitment and differentiation
More study should be done 1. Molecular characterization of undetecta ble abnormalities on the cytogenetic level 2. Characterization of additional chromosomal or molecular genetic abnormalities e.g. t(11; 17 in the well defined favorable cytogenetic group may influence clinical outcome 3. Characterization of cooperating genetic abnormalities may affect treatment response in stepwise leukemogenesis
More study should be done 1. Molecular characterization of undetectable abnormalities on the cytogenetic level 2. Characterization of additional chromosomal or molecular genetic abnormalities [e.g. t(11;17)] in the welldefined favorable cytogenetic group may influence clinical outcome 3. Characterization of cooperating genetic abnormalities may affect treatment response in stepwise leukemogenesis
Hematopoiesis: a model of svstems biomedicine Common Myeloid c○ Common Lymphoid Progenitor(c Progenitor (CLP) cD33·,cD34+,cD38 Hematopoietic CD10*, CD38+, TaT Stem Cell(HSC) cD34+,cD38 EMP BFU-E BFU-meg GMP CFU-baso T-cell B-cell cD33+ CD34+ cD13+,cD33 CD34+ progenitor progenitor CD34+ cD34+ CD2+, CD4+ CD38+,cD34+ IL-3 CD5+, CD7+ cD24+,cD19+ GM-CSF lL·11 L-3 L-6 lL·10 L·1 Pre-Pre-B GM-CSF CFU-E CFU-meg CFU-M CFU-G CFU-Eos IL-4. SF CD36 CSF-1 G-CSF GM-CSF GM-CSF Pre-B IL-4. IL-5 GM-CSF L-6.L-11 B cell IL-6. TP CSF.t lL-8) ast ce L-4.L-5.lL6 RBC platelets Mono Important players: Hematopoietic stem cells, cytokines, microenvironment
Hematopoiesis: a model of systems biomedicine Common Myeloid Progenitor (CMP) Hematopoietic Stem Cell (HSC) Common Lymphoid Progenitor (CLP) GMP EMP Important players: Hematopoietic stem cells, cytokines, microenvironment
